Heterocyclic compounds useful as pim kinase inhibitors

ABSTRACT

The present application is concerned with heterocyclic compounds that inhibit the activity of Pim kinases and are useful in the treatment of diseases related to the activity of Pim kinases including, e.g., cancers and other diseases.

FIELD OF THE INVENTION

The present application is concerned with pharmaceutically activecompounds. The disclosure provides compounds as well as theircompositions and methods of use. The compounds inhibit the activity ofPim kinases and are useful in the treatment of diseases related to theactivity of Pim kinases including, e.g., cancers and other diseases.

BACKGROUND OF THE INVENTION

Protein kinases regulate diverse biological processes including cellgrowth, survival, differentiation, organ formation, morphogenesis,neovascularization, tissue repair, and regeneration, among others.Protein kinases also play specialized roles in a host of human diseasesincluding cancer. The three members of the Pim kinase family, oneexample of a protein kinase family, were initially identified aspreferential integration sites of Moloney leukemia virus in mouse modelsof cancer. Although possessing modest but measurable oncogenic activityalone, they potentiate pro-proliferative and pro-survival oncogenes,e.g., causing a dramatic acceleration of lymphomagenesis inMyc-transgenic or Bc12-transgenic mice. Mikkers et al., Nature Genet.,2002, 32, 153-159; Shinto et al., Oncogene, 1995, 11, 1729-35.

The three non-receptor serine/threonine kinases Pim1, Pim2 and Pim3regulate cell proliferation and survival by impacting gene transcriptionand protein translation. Zippo, et al., Nature Cell Biol., 2007, 9,932-44; Schatz, et al., J. Exp. Med., 2011, 208, 1799-1807. As opposedto numerous other protein kinases which require activation byphosphorylation, the Pim kinases are constitutively activated and familymembers have overlapping substrate targets and biological functions,with differences between family members dictated, in part, by theirvaried tissue distribution. Expression of the Pim kinases is induced bycytokines and growth factors. Among the cytokines activating Pim kinaseexpression are cytokines which signal through the JAK/STAT pathway. Pimkinases act in parallel to the PI3K/AKT pathway, and they share severalphosphorylation targets (e.g., pBAD, p4EBP1). Inhibitors of Pim kinasesmay therefore potentiate regimens including inhibitors of either the JAKpathway or the PI3K/AKT pathway.

Overexpression of Pim kinases is detected in a wide variety ofhematologic and solid cancers. Overexpression of various family membershave been noted in multiple myeloma, A ML, pancreatic and hepatocellularcancers. Claudio et al., Blood, 2002, 100, 2175-86; Amson et al., Proc.Nat. Acad. Sci., USA, 1989, 86, 8857-61; Mizuki et al., Blood, 2003,101, 3164-73; Li et al., Canc. Res., 2006, 66, 6741-7; Fujii et al.,Int. J. Canc., 2005, 114, 209-18. Pim1overexpression is associated withpoor prognosis in mantle cell lymphoma, esophageal and head and neckcancers. Hsi et al., Leuk. Lymph., 2008, 49, 2081-90; Liu et al., J.Surg. Oncol., 2010, 102, 683-88; Peltola et al., Neoplasia, 2009, 11,629-36. Pim2 overexpression is associated with an aggressive clinicalcourse in a subset of DLBCL patients. Gomez-Abad et al., Blood, 2011,118, 5517-27. Overexpression is often seen where Myc is overexpressedand Pim kinases can convey resistance to traditional chemotherapeuticagents and radiation. Chen et al., Blood, 2009, 114, 4150-57; Isaac etal., Drug Resis. Updates, 2011, 14, 203-11; Hsu et al., Cancer Lett.,2012, 319, 214; Peltola et al., Neoplasia, 2009, 11, 629-36.

As such, these data indicate that inhibition of Pim kinases will beuseful to provide therapeutic benefit in cancer patients.

Data from mice deficient for one or multiple Pim kinase family memberssuggests that pan-Pim inhibitor would have a favorable toxicity profile.Triple knockout mice are viable, but are slightly smaller than theirwild type littermates. Mikkers et al., Mol. Cell. Biol., 2004, 24.6104-15. Since Pim kinases are also involved in a variety of immunologicand inflammatory responses and these indications require drug agentswith fewer side effects, Pim kinase inhibitors are expected to be usefulin treating patients with colitis (Shen et al., Dig. Dis. Sci., 2012,57, 1822-31), peanut allergy (Wang et al., J. All. Clin. Immunol., 2012,130, 932-44), multiple sclerosis and lupus (Davis et al., “SmallMolecule Dual Antagonist of Pim 1 and 3 Kinases Ameliorate ExperimentalAutoimmune Encephalomyelitis”, 26^(th) Congress of the EuropeanCommittee for Treatment and Research in Multiple Sclerosis, 13-16 Oct.2010, Gothenburg, Sweden, Poster P436; Robinson et al., J. Immunol.,2012, 188, 119.9) and rheumatoid arthritis (Yang et al., Immunol. 2010,131, 174-182) and other immunological and inflammatory disorders.

The Pim kinases have therefore been identified as useful targets fordrug development efforts. Swords et al., Curr. Drug Targets, 2011,12(1-4), 2059-66; Merkel et al., Exp. Opin. Investig. Drugs, 2012, 21,425-38; Morwick et al., Exp. Opin. Ther. Patents, 2010, 20(2), 193-212.

Accordingly, there is a need for new compounds that inhibit Pim kinases.The present application describes new inhibitors of Pim kinases that areuseful for treating diseases associated with the expression or activityof one or more Pim kinases, e.g., cancer and other diseases.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinconstituent variables are defined herein.

The present invention further provides pharmaceutical compositioncomprising a compound of the invention, or a pharmaceutically acceptablesalt or a stereoisomer thereof, and at least one pharmaceuticallyacceptable carrier.

The present invention further provides methods of inhibiting Pim kinasescomprising contacting a Pim kinase with a compound of the invention, ora pharmaceutically acceptable salt or a stereoisomer thereof.

The present invention further provides methods of treating disease in apatient comprising administering a therapeutically effective amount of acompound of the invention, or a pharmaceutically acceptable salt or astereoisomer thereof, to the patient.

DETAILED DESCRIPTION I. Compounds

The present invention provides Pim kinase-inhibitiong componds such as acompound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

R¹ is selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ halaolkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₁₋₁₀ cycloalkyl, 5-14membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₆alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a),SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹ are each optionallysubstituted with 1, 2, 3, or 4 R^(b) substituents;

-   -   each R^(b) substituent is independently selected from halo, C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 membered        heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂, NHOR^(c),        OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),        OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),        NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c),        NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c), NR^(c)(O)NR^(c)R^(c),        NR^(c)C(O)R^(c), NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c),        S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) and S(O)₂NR^(c)R^(c);        wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀        aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄        alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10        membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each        optionally substituted with 1-3 independently selected R^(d)        substituents;

or two adjacent R^(b) substituents on the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring of R¹,taken together with the atoms to which they are attached, form a fusedphenyl ring, a fused 5- or 6-membered heterocycloalkyl ring, a fused 5-or 6-membered heteroaryl ring, or a fused C₅₋₆ cycloalkyl ring, whereinthe fused 5- or 6-membered heterocycloalkyl ring and fused 5- or6-membered heteroaryl ring each have 14 heteroatoms as ring membersselected from N, O and S and wherein the fused phenyl ring, fused 5- or6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroarylring, and fused C₅₋₆ cycloalkyl are each optionally substituted with 1or 2 independently selected R^(r) substituents;

each R^(a), is independently selected from H, CN, C₁₋₆ halaolkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(a), areeach optionally substituted with 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(d) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH₂,NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), whereinthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl ofR^(d) are each further optionally substituted with 1-3 independentlyselected R^(r) substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄alkyl-, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 Rn substituents independently selected from C₁₋₄alkyl, C₁₋₄haloalkyl, halo, CN, R^(o), NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o),NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o),S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o),NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o);

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1-3 independently selected R^(p)substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆halaolkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i),NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i),OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinthe C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-6 membered heteroaryl of R^(h) are each further optionallysubstituted by 1, 2, or 3 R^(j) substituents independently selected fromC₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k),SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k); or twoR^(h) groups attached to the same carbon atom of the 4- to 10-memberedheterocycloalkyl taken together with the carbon atom to which theyattach form a C₃₋₆ cycloalkyl or 4- to 6-membered heterocycloalkylhaving 1-2 heteroatoms as ring members selected from O, N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; and

each R^(e), R^(i), R^(k), R^(o) or R^(p) is independently selected fromH, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl,C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl of R^(e), R^(i), R^(k), R^(o) or R^(p) are eachoptionally substituted with 1, 2 or 3 R^(r) substituents;

each R^(r) is independently selected from OH, CN, amino, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₃₋₆ cycloalkyl, NHR⁹, NR⁹R⁹, andC₁₋₄ haloalkoxy, wherein the C₁₋₄ alkyl of R^(r) is optionallysubstituted with OH, CN, NH₂, C₁₋₄ alkoxy, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl, wherein each R⁹ is independently H or C₁₋₆alkyl;

R² is H, OH, OR^(a), NHR^(a), or NR^(a)R^(a);

R³ is H, halo or CN;

each R⁴ is independently selected from H, halo, CN, OH, NH₂, NHCH₃,N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy,ethenyl, C₂₋₄ alkynyl and cyclopropyl, wherein the C₁₋₄ alkyl and C₁₋₄alkoxy are each optionally substituted with CN or CH₃O—;

each R⁵ is independently selected from H, halo, CN, OH, NH₂, NHCH₃,N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy,ethenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, and 5- or 6-memberedheteroaryl, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionallysubstituted with CN or CH₃O—;

each R⁶ is independently selected from H, halo, CN, OH, NH₂, NHCH₃,N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy,ethenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, and 5- or 6-memberedheteroaryl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₆₋₁₀aryl, and 5- or 6-membered heteroaryl are each optionally substitutedwith OH, CN or CH₃O—;

or any two R⁶ substituents attached to the same carbon atom, takentogether with the carbon atom to which they are attached, form C₃₋₁₀cycloalkyl or a 4-, 5-, or 6-membered heterocycloalkyl, wherein theC₃₋₁₀ cycloalkyl and 4-, 5-, or 6-membered heterocycloalkyl are eachoptionally substituted with 1-3 independently selected R^(p)substituents;

R⁸ is H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-,wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl and C₃₋₆ cycloalkyl-C₁₋₄ alkylare each optionally substituted with OH, CN or CH₃O—;

X is N or CR⁷, wherein R⁷ is H, halo, NH₂, C₁₋₄ alkoxy, C₁₋₄ alkyl-NH—or (C₁₋₄ alkyl)₂N—;

the subscript m is an integer of 1 or 2;

the subscript n is an integer of 1, 2 or 3; and

the subscript p is an integer of 1, 2 or 3.

In some embodiments, the present invention provides a compound havingFormula (II):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinR¹⁰ is halo, CN, OH, NH₂, NHCH₃, N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₂haloalkyl, C₁₂ haloalkoxy, ethenyl, C₂₋₄alkynyl or C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, wherein C₁₋₄ alkyl and C₁₋₄alkoxy, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered hetero aryl areeach optionally substituted with OH, CN or CH₃O—.

In some embodiments, the present invention provides a compound havingformula

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In some embodiments, the present invention provides a compound havingformula (IV):

In some embodiments, the present invention provides a compound havingformula (V):

In some embodiments, the present invention provides a compound havingformula (V):

In some embodiments, R¹ is H, halo, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₆ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, OR^(a), NHR^(a), NR^(a)R^(a), wherein the C₁₋₆ alkyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl and4-10 membered heterocycloalkyl of R¹ are each optionally substitutedwith 1, 2, 3, or 4 R^(b) substituents;

or two adjacent R^(b) substituents on the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring of R¹,taken together with the atoms to which they are attached, form a fusedphenyl ring, a fused 5- or 6-membered heterocycloalkyl ring, a fused 5-or 6-membered heteroaryl ring or a fused C₅₋₆ cycloalkyl ring, whereinthe fused 5- or 6-membered heterocycloalkyl ring and fused 5- or6-membered heteroaryl ring each have 14 heteroatoms as ring membersselected from N, O and S and wherein the fused phenyl ring, fused 5- or6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ringand fused C₅₋₆ cycloalkyl are each optionally substituted with 1 or 2independently selected R^(r) substituents.

In some embodiments, R¹ is H, halo, C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₆cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl,OR^(a), NHR^(a), NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-14 membered heteroaryl and 4-10 membered heterocycloalkylof R¹ are each optionally substituted with 1, 2, 3, or 4 R^(b)substituents;

or two adjacent R^(b) substituents on the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring of R¹,taken together with the atoms to which they are attached, form a fusedphenyl ring, a fused 5- or 6-membered heterocycloalkyl ring, a fused 5-or 6-membered heteroaryl ring or a fused C₅₋₆ cycloalkyl ring, whereinthe fused 5- or 6-membered heterocycloalkyl ring and fused 5- or6-membered heteroaryl ring each have 14 heteroatoms as ring membersselected from N, O and S and wherein the fused phenyl ring, fused 5- or6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ringand fused C₅₋₆ cycloalkyl are each optionally substituted with 1 or 2independently selected R^(r) substituents.

In some embodiments, R¹ is selected from C₁₋₆ alkyl, C₂₋₆ alkynyl, C₆₋₁₀aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, NHR^(a), and NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, and4-10 membered heterocycloalkyl, of R¹ are each optionally substitutedwith 1, 2, 3, or 4 R^(b) substituents.

In some embodiments, R¹ is selected from ethyl, ethynyl, phenyl,cyclopropyl, pyrazolyl, pyridyl, quinolinyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, azepanyl, morpholino, thiomorpholino,indolinyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl,2-oxo-5-azabicyclo[2.2.1]heptan-5-yl,6-oxo-3-azabicyclo[3.1.1]heptan-3-yl,2.5-diazabicyclo[2.2.1]heptan-2-yl, NHR^(a), NR^(a)R^(a),tetrahydropyranyl, 4-oxodihydro-1H-pyrido[1,2-a]pyrazin-2 (6H,7H,8H,9H,9aH)-yl), oxazepanyl, 2-azaspiro[3.3]heptan-2-yl,3-oxa-9-azabicyclo[3.3.1]nonan-9-yl, 1,2-oxazinan-2-yl,dihydro-1H-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl,6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl, 2H-benzo[b][1,4]oxazin-4(3H)-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, diazepanyl,4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl,1,1-dioxido-1,2,6-thiadiazinan-2-yl, 1,2,3,4-tetrahydroquinolinyl,5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl,7-azabicyclo[2.2.1]heptan-7-yl, 1,1-dioxidoisothiazolidin-2-yl,3-oxopiperazin-1-yl, 2-oxopyrrolidin-1-yl,6-oxohexahydropyrrolo[1,2-a]pyrazin-2 (1H)-yl, 5-oxopiperazin-1-yl, and3-oxo-1,4-diazepan-1-yl, wherein the ethyl, ethynyl, phenyl,cyclopropyl, pyrazolyl, pyridyl, quinolinyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, azepanyl, morpholino, thiomorpholino,indolinyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl,2-oxo-5-azabicyclo[2.2.1]heptan-5-yl,6-oxo-3-azabicyclo[3.1.1]heptan-3-yl,2.5-diazabicyclo[2.2.1]heptan-2-yl, NHR^(a), NR^(a)R^(a),tetrahydropyranyl, 4-oxodihydro-1H-pyrido[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl), oxazepanyl, 2-azaspiro[3.3]heptan-2-yl,3-oxa-9-azabicyclo[3.3.1]nonan-9-yl, 1,2-oxazinan-2-yl,dihydro-1H-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl,6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl,2H-benzo[b][1,4]oxazin-4(3H)-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl,diazepanyl, 4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6 (7H)-yl,1,1-dioxido-1,2,6-thiadiazinan-2-yl, 1,2,3,4-tetrahydroquinolinyl,5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl,7-azabicyclo[2.2.1]heptan-7-yl, 1,1-dioxidoisothiazolidin-2-yl,3-oxopiperazin-1-yl, 2-oxopyrrolidin-1-yl,6-oxohexahydropyrrolo[1,2-a]pyrazin-2 (1H)-yl, 5-oxopiperazin-1-yl, and3-oxo-1,4-diazepan-1-yl of R¹ are each optionally substituted with 1, 2,3, or 4 R^(b) substituents.

In some embodiments, R¹ is selected from ethyl, ethynyl, phenyl,cyclopropyl, pyrazolyl, pyridyl, quinolinyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, azepanyl, morpholino, thiomorpholino,indolinyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl,2-oxo-5-azabicyclo[2.2.1]heptan-5-yl,6-oxo-3-azabicyclo[3.1.1]heptan-3-yl,2.5-diazabicyclo[2.2.1]heptan-2-yl, NHR^(a), and NR^(a)R^(a), whereinthe ethyl, ethynyl, phenyl, cyclopropyl, pyrazolyl, pyridyl, quinolinyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl,morpholino, thiomorpholino, indolinyl,3-oxa-8-azabicyclo[3.2.1]octan-8-yl,2-oxo-5-azabicyclo[2.2.1]heptan-5-yl,6-oxo-3-azabicyclo[3.1.1]heptan-3-yl,2.5-diazabicyclo[2.2.1]heptan-2-yl, of R¹ are each optionallysubstituted with 1, 2, 3, or 4 R^(b) substituents.

In some embodiments, R¹ is selected from 2-azabicyclo[2.2.1]heptan-2-yl,8-azabicyclo[3.2.1]octan-8-yl, 5-oxopiperazin-1-yl,(R)-4-oxodihydro-1H-pyrido[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl,azepan-1-yl, 1,4-oxazepan-4-yl, 2-azaspiro[3.3]heptan-2-yl,piperidin-1-yl, 3-oxa-9-azabicyclo[3.3.1]nonan-9-yl,tetrahydro-2H-1,2-oxazin-2-yl (also know as 1,2-oxazinan-2-yl),dihydro-1H-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl, azetidin-1-yl,3-oxopiperazin-1-yl, 6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl,2H-benzo[b][1,4]oxazin-4(3H)-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl,1,4-diazepan-1-yl, 4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl,1,1-dioxido-1,2,6-thiadiazinan-2-yl, 3,4-dihydro-2H-quinolin-4-yl,4-morpholinyl, 3-oxopiperazin-1-yl,5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl,3-oxo-1,4-diazepan-1-yl, 7-azabicyclo[2.2.1]heptan-7-yl,1,1-dioxidoisothiazolidin-2-yl, pyridin-2-yl, pyridin-3-yl,pyrrolidin-1-yl, 1,4-piperizin-4-yl, NHR^(a), and NR^(a)R^(a), whereinthe 2-azabicyclo[2.2.1]heptan-2-yl, 8-azabicyclo[3.2.1]octan-8-yl,5-oxopiperazin-1-yl,(R)-4-oxodihydro-1H-pyrido[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl,azepan-1-yl, 1,4-oxazepan-4-yl, 2-azaspiro[3.3]heptan-2-yl,piperidin-1-yl, 3-oxa-9-azabicyclo[3.3.1]nonan-9-yl,tetrahydro-2H-1,2-oxazin-2-yl (also know as 1,2-oxazinan-2-yl),dihydro-1H-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl, azetidin-1-yl,3-oxopiperazin-1-yl, 6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl,2H-benzo[b][1,4]oxazin-4(3H)-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl,1,4-diazepan-1-yl, 4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl,1,1-dioxido-1,2,6-thiadiazinan-2-yl, 3,4-dihydro-2H-quinolin-4-yl,4-morpholinyl, 3-oxopiperazin-1-yl,5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl,3-oxo-1,4-diazepan-1-yl, 7-azabicyclo[2.2.1]heptan-7-yl,1,1-dioxidoisothiazolidin-2-yl, pyridin-2-yl, pyridin-3-yl,pyrrolidin-1-yl, 1,4-piperizin-4-yl, of R¹ are each optionallysubstituted with 1, 2, 3, or 4 R^(b) substituents.

In some embodiments, each R^(b) substituent is independently selectedfrom halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₁₀ cycloalkyl, CN, OH, OR^(c),C(O)NR^(c)R^(c), C(O)OR^(c), S(O)₂R^(c) and S(O)₂NR^(c)R^(c); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₃₋₁₀ cycloalkyl of R^(b) are eachoptionally substituted with 1-3 independently selected R^(d)substituents;

or two adjacent R^(b) substituents on the C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring of R¹,taken together with the atoms to which they are attached, form a fusedphenyl ring, a fused 5- or 6-membered heterocycloalkyl ring, a fused 5-or 6-membered heteroaryl ring, or a fused C₅₋₆ cycloalkyl ring, whereinthe fused 5- or 6-membered heterocycloalkyl ring and fused 5- or6-membered heteroaryl ring each have 14 heteroatoms as ring membersselected from N, O and S and wherein the fused phenyl ring, fused 5- or6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroarylring, and fused C₅₋₆ cycloalkyl are each optionally substituted with 1or 2 independently selected R^(r) substituents.

In some embodiments, R^(r) is selected from ethyl, isopropyl,3-methoxypropyl, Br, I, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy,2-fluorophenyl, phenyl, 3,5-difluorophenyl, 2-cyanophenyl,2-cyano-6-fluorophenyl, 2-methoxyphenyl, 2-trifluomethoxyphenyl,2,6-difluoro-4-hydroxyphenyl, 2,6-difluoro-4-methoxyphenyl,2,6-difluoro-4-dimethylaminomethylphenyl,2,6-difluoro-4-hydroxymethylphenyl, 2-methylsulfonylphenyl,2-chloro-6-methoxyphenyl, 2-carbamoyl-6-methoxyphenyl,3-fluoro-4-methylcarbamoylphenyl, 3-fluoro-2-pyridyl,2-methyoxy-5-pyridyl, 3-fluoropyridyl, 1-pyrrolidinyl, 1-azetidinyl,3-fluoropyrrolidin-1-yl, 3-cyanopyrroolidin- l -yl,3-fluoroazetidin-1-yl, morpholin-4-yl, 3-methoxy-piperidin-1-yl,3-cyclopropyl-ethynyl, ethyl(methyl)amino, cyclopropyl(methyl)amino,methyl(2,2,2,trifluoroethyl)amino, 2-fluoroethyl(methyl)amino,methyl(tetrahydrofuran-3-yl)amino, cyclobutyl(methyl)amino,dimethylamino, 2-fluoroethylamino, 2,2-difluoroethylamino,3,3-difluoropiperdin-1-yl, 3-fluoro-4-hydroxypiperidin-1-yl,4-methylpiperazin-1-yl, tetrahydro-2H-pyran-4-yl, 3-methylmorpholino,2-methylmorpholino, 2-methylpyrrolidin-1-yl, 2,5-dimethylmorpholino,2,5-dimethylpyrrolidin-1-yl, 2,6-dimethylmorpholino,4,4-difluoropiperidin-1-yl, 4-hydroxy-4-methylpiperidin-1-yl,2-methylpiperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-cyanopiperidin-1-yl,4-methylpiperidin-1-yl, 3-methoxypyrrolidin-1-yl,(2-methoxyethyl)(methyl)amino, 2-(methoxymethyl)pyrrolidin-1-yl,1-cyclopropylethylamino, 3-methylbutan-2-ylamino, methyl(propyl)amino,isopropyl(methyl)amino, 2-ethylpiperidin-1-yl,2-difluoromethylpiperidin-1-yl, 6-fluoroquinolin-8-yl,5-fluoroquinolin-8-yl, 6-trifluoromethylpyridin-3-yl,1-ethyl-1-H-pyrazol-4-yl, 1,3-dimethyl-1-H-pyrazol-4-yl,1-methyl-1-H-pyrazol-4-yl, 3-methyl-1-H-pyrazol-4-yl, 1-H-pyrazol-4-yl,2,2-difluoroethyl(methyl)amino, thiomorpholino,4-(dimethylsulfamoyl)piperazin-1-yl, 4-methyl-3-oxopiperazin-1-yl,azepan-1-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 2-oxo-pyrrolidin-1-yl,indolin-1-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl,6-oxa-3-azabicyclo[3.1.1]heptan-3-yl,4-(dimethylcarbamoyl)piperidin-1-yl, (methyl)(phenyl)amino,6-oxohexahydropyrrolo [1,2-alpyrazin-2(1H)-yl,2-methyl-4-(methylsulfonyl)piperazin-1-yl,2-methyl-4-(methylcarboxy)piperazin-1-yl,2-(methylcarboxy)-2,5-diazabicyclo[2.2.1]heptan-5-yl,2-azabicyclo[2.2.1]heptan-2-yl, (2-fluorophenyl)(methyl)amino,3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl, (R)-2,4-dimethyl-5-oxopiperazin-1-yl,(R)-4-oxodihydro-1H-pyridol[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl,4-methoxyazepan-1-yl, 1,4-oxazepan-4-yl, 6-hydroxy-2-azasp iro[3.3]heptan-2-yl, 4-hydroxyazepan-1-yl, (R)-3-methylpiperidin-1-yl,3-oxa-9-azabicyclo[3.3.1]nonan-9-yl, 2-azaspiro[3.3]heptan-2-yl,tetrahydro-2H-1,2-oxazin-2-yl (also know as 1,2-oxazinan-2-yl),dihydro-1H-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl, 3-methylazetidin-1-yl,(S)-2,4-dimethyl-3-oxopiperazin-1-yl, (S)-3-methylpiperidin-1-yl,4-cyclopropyl-3-oxopiperazin-1-yl, 4-isopropyl-3-oxopiperazin-1-yl, 3,3-dimethylazetidin-1-yl, 4-isobutyl-3-oxopiperazin-1-yl,3-methoxy-3-methylazetidin-1-yl,2-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl,5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl,7-oxa-2-azaspiro[3.5]nonan-2-yl, 3-ethoxyazetidin-1-yl,(S)-2-(hydroxymethyl)azetidin-1-yl,4-(methylsulfonyl)-1,4-diazepan-1-yl, 2-fluorophenylamino,1-carbomethoxy-1,4-diazepan-4-yl,1-methyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl,6-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl, 2-cyanophenylamino,3,4-dihydro-2H-quinolin-4-yl, 4-methoxypiperidin-1-yl,2-(hydroxymethyl)morpholino, 4-(2-methoxyethyl)-3-oxopiperazin-1-yl,5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl,4-methyl-3-oxo-1,4-diazepan-1-yl, 7-azabicyclo[2.2.1]heptan-7-yl,8-fluoro-3,4-dihydro-2H-quinolin-4-yl, 1,1-dioxidoisothiazolidin-2-yl,(3-(difluoromethoxy)pyridin-2-yl)(methyl)amino,(2-cyanocyclopentyl)(methyl)amino,(2,6-dimethylpyridin-3-yl)(methyl)amino,(3-fluoropyridin-2-yl)(methyl)amino,(4-(trifluoromethyl)pyridin-3-yl)(methyl)amino,(6-methoxy-2-methylpyridin-3-yl)(methyl)amino,(3-fluoropyridin-4-yl)(methyl)amino,(4-methylpyridin-3-yl)(methyl)amino, (2-methylcyclobutyl)(methyl)amino,(4-methoxyphenyl)(methyl)amino, (3-methylpyrazin-2-yl)(methyl)amino,(4-methoxypyridin-3-yl)(methyl)amino,(methyl)(tetrahydro-2H-pyran-3-yl)amino, (2-methoxyphenyl)(methyl)amino,(imidazo[1,2-a]pyridin-6-yl)(methyl)amino,(methyl)((R)-tetrahydrofuran-3-yl)amino,(2S,4R)-4-methoxy-2-methylpyrrolidin-1-yl,(2R,4R)-4-methoxy-2-methylpyrrolidin-1-yl,(2S,4S)-4-methoxy-2-methylpyrrolidin-1-yl,(2R,4S)-4-methoxy-2-methylpyrrolidin-1-yl,(2R,4S)-4-methoxy-2-methylpiperidin-1-yl,(2S,4R)-4-methoxy-2-methylpiperidin-1-yl,(2R,4R)-4-methoxy-2-methylpiperidin-1-yl,(3R,4R)-3-fluoro-4-methoxypiperidin-1-yl,(3S,4S)-3-fluoro-4-(2-methoxyethoxy)piperidin-1-yl,(2R,4S)-4-hydroxy-2-methylpyrrolidin-1-yl,(2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl, (S)-2-methylazetidin-1-yl,(R)-2-methylazetidin-1-yl, 1-carboethoxy-1,4-piperizin-4-yl,(R)-2-methylpiperidin-1-yl and (S)-2-methylpiperidin-1-yl.

In some embodiments, R¹ is selected from ethyl, isopropyl,3-methoxypropyl, Br, I, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy,2-fluorophenyl, phenyl, 3,5-difluorophenyl, 2-cyanophenyl,2-cyano-6-fluorophenyl, 2-methoxyphenyl, 2-trifluomethoxyphenyl,2,6-difluoro-4-hydroxyphenyl, 2,6-difluoro-4-methoxyphenyl,2,6-difluoro-4-dimethylaminomethylphenyl,2,6-difluoro-4-hydroxymethylphenyl, 2-methylsulfonylphenyl,2-chloro-6-methoxyphenyl, 2-carbamoyl-6-methoxyphenyl,3-fluoro-4-methylcarbamoylphenyl, 3-fluoro-2-pyridyl,2-methyoxy-5-pyridyl, 3-fluoropyridyl, 1-pyrrolidinyl, 1-azetidinyl,3-fluoropyrrolidin-1-yl, 3-cyanopyrroolidin-1-yl, 3-fluoroazetidin-1-yl,morpholin-4-yl, 3-methoxy-piperidin-1-yl, 3-cyclopropyl-ethynyl,ethyl(methyl)amino, cyclopropyl(methyl)amino,methyl(2,2,2,trifluoroethyl)amino, 2-fluoroethyl(methyl)amino,methyl(tetrahydrofuran-3-yl)amino, cyclobutyl(methyl)amino,dimethylamino, 2-fluoroethylamino, 2,2-difluoroethylamino,3,3-difluoropiperdin-1-yl, 3-fluoro-4-hydroxypiperidin-1-yl,4-methylpiperazin-1-yl, tetrahydro-2H-pyran-4-yl, 3-methylmorpholino,2-methylmorpholino, 2-methylpyrrolidin-1-yl, 2,5-dimethylmorpholino,2,5-dimethylpyrrolidin-1-yl, 2,6-dimethylmorpholino,4,4-difluoropiperidin-1-yl, 4-hydroxy-4-methylpiperidin-1-yl,2-methylpiperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-cyanopiperidin-1-yl,4-methylpiperidin-1-yl, 3-methoxypyrrolidin-1-yl,(2-methoxyethyl)(methyl)amino, 2-(methoxymethyl)pyrrolidin-1-yl,1-cyclopropylethylamino, 3-methylbutan-2-ylamino, methyl(propyl)amino,isopropyl(methyl)amino, 2-ethylpiperidin-1-yl,2-difluoromethylpiperidin-1-yl, 6-fluoroquinolin-8-yl,5-fluoroquinolin-8-yl, 6-trifluoromethylpyridin-3-yl,1-ethyl-1-H-pyrazol-4-yl, 1,3-dimethyl-1-H-pyrazol-4-yl,1-methyl-1-H-pyrazol-4-yl, 3-methyl-1-H-pyrazol-4-yl, 1-H-pyrazol-4-yl,2,2-difluoroethyl(methyl)amino, thiomorpholino,4-(dimethylsulfamoyl)piperazin-1-yl, 4-methyl-3-oxopiperazin-1-yl,azepan-1-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 2-oxo-pyrrolidin-1-yl,indolin-1-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl,6-oxa-3-azabicyclo[3.1.1]heptan-3-yl,4-(dimethylcarbamoyl)piperidin-1-yl, (methyl)(phenyl)amino,6-oxohexahydropyrrolo [1,2-alpyrazin-2(1H)-yl,2-methyl-4-(methylsulfonyl)piperazin-1-yl,2-methyl-4-(methylcarboxy)piperazin-1-yl, and2-(methylcarboxy)-2,5-diazabicyclo[2.2.1]heptan-5-yl, or stereoisomersthereof.

In some embodiments, R¹ is selected from 2-azabicyclo[2.2.1]heptan-2-yl,(2-fluorophenyl)(methyl)amino, 3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl,(R)-2,4-dimethyl-5-oxopiperazin-1-yl,(R)-4-oxodihydro-1H-pyrido[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl,4-methoxyazepan-1-yl, 1,4-oxazepan-4-yl,6-hydroxy-2-azaspiro[3.3]heptan-2-yl, 4-hydroxyazepan-1-yl,(R)-3-methylpip eridin-1-yl, 3-oxa-9-azabicyclo[3.3.1]nonan-9-yl,2-azaspiro[3.3]heptan-2-yl, 3-fluoro-4-hydroxypiperidin-1-yl,tetrahydro-2H-1,2-oxazin-2-yl (also know as 1,2-oxazinan-2-yl),dihydro-1H-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl, 3-methylazetidin-1-yl,(S)-2,4-dimethyl-3-oxopiperazin-1-yl, (S)-3-methylpiperidin-1-yl,4-cyclopropyl-3-oxopiperazin-1-yl, 4-isopropyl-3-oxopiperazin-1-yl,3,3-dimethylazetidin-1-yl, 4-i s obutyl-3-oxopiperazin-1-yl,3-methoxy-3-methyl azetidin-1-yl, 2-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl,5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl,7-oxa-2-azaspiro[3.5]nonan-2-yl, 3-ethoxyazetidin-1-yl,(S)-2-(hydroxymethyl)azetidin-1-yl,4-(methylsulfonyl)-1,4-diazepan-1-yl, 2-fluorophenylamino,1-carbomethoxy-1,4-diazepan-4-yl,1-methyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl,6-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl, 2-cyanophenylamino,3,4-dihydro-2H-quinolin-4-yl, 4-methoxypiperidin-1-yl,2-(hydroxymethyl)morpholino, 4-morpholinyl,4-(2-methoxyethyl)-3-oxopiperazin-1-yl,5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl,4-methyl-3-oxo-1,4-diazepan-1-yl, 7-azabicyclo[2.2.1]heptan-7-yl,8-fluoro-3,4-dihydro-2H-quinolin-4-yl,1,1-(3-(difluoromethoxy)pyridin-2-yl)(methyl)amino,(2-cyanocyclopentyl)(methyl)amino,(2,6-dimethylpyridin-3-yl)(methyl)amino,(3-fluoropyridin-2-yl)(methyl)amino,(4-(trifluoromethyl)pyridin-3-yl)(methyl)amino,(6-methoxy-2-methylpyridin-3-yl)(methyl)amino,(3-fluoropyridin-4-yl)(methyl)amino,(4-methylpyridin-3-yl)(methyl)amino, (2-methylcyclobutyl)(methyl)amino,(4-methoxyphenyl)(methyl)amino, (3-methylpyrazin-2-yl)(methyl)amino,(4-methoxypyridin-3-yl)(methyl)amino,(methyl)(tetrahydro-2H-pyran-3-yl)amino, (2-methoxyphenyl)(methyl)amino,(imidazo[1,2-a]pyridin-6-yl)(methyl)amino,(methyl)((R)-tetrahydrofuran-3-yl)amino,(2S,4R)-4-methoxy-2-methylpyrrolidin-1-yl,(2R,4R)-4-methoxy-2-methylpyrrolidin-1-yl,(2S,4S)-4-methoxy-2-methylpyrrolidin-1-yl,(2R,4S)-4-methoxy-2-methylpyrrolidin-1-yl,(2R,4S)-4-methoxy-2-methylpiperidin-1-yl,(2S,4R)-4-methoxy-2-methylpiperidin-1-yl,(2R,4R)-4-methoxy-2-methylpiperidin-1-yl,(3R,4R)-3-fluoro-4-methoxypiperidin-1-yl,(3S,4S)-3-fluoro-4-(2-methoxyethoxy)piperidin-1-yl,(2R,4S)-4-hydroxy-2-methylpyrrolidin-1-yl,(2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl, (S)-2-methylazetidin-1-yl,(R)-2-methylazetidin-1-yl, 1-carboethoxy-1,4-piperizin-4-yl,(R)-2-methylpiperidin-1-yl and (S)-2-methylpiperidin-1-yl.

In some embodiments, each Rd is independently selected from H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, and C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkylof R^(a) are each optionally substituted with 1, 2, 3, 4, or 5 R^(d)substituents.

In some embodiments, each Rd is independently selected from H, methyl,ethyl, n-propyl, isopropyl, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CH₂CH₂OCH₃,cyclopropyl, cyclobutyl, tetrahydrofuranyl (e.g.,(R)-tetrahydrofuran-3-yl), phenyl, 1-cyclopropylethyl,3-methylbutan-2-yl, 2-fluorophenyl, 3-(difluoromethoxy)pyridin-2-yl,2-cyanocyclopentyl, 2,6-dimethylpyridin-3-yl, 3-fluoropyridin-2-yl,4-(trifluoromethyl)pyridin-3-yl, 6-methoxy-2-methylpyridin-3-yl,3-fluoropyridin-4-yl, 4-methylpyridin-3-yl, 2-methylcyclobutyl,4-methoxyphenyl, 3-methylpyrazin-2-yl, 4-methoxypyridin-3-yl,tetrahydropyranyl (e.g., tetrahydro-2H-pyran-3-yl), 2-methoxyphenyl,imidazo[1,2-a]pyridin-6-yl, cyclopropylmethyl, 2-methoxyethyl,2-cyanophenyl, and (2-cyanocyclopentyl)methyl.

In some embodiments, each R^(a), is independently selected from H,methyl, ethyl, n-propyl, isopropyl, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F,—CH₂CH₂OCH₃, cyclopropyl, cyclobutyl, tetrahydrofuranyl, phenyl,1-cyclopropylethyl, 3-methylbutan-2-yl, cyclopropylmethyl, and2-methoxyethyl.

In some embodiments, each R^(a), is independently selected from H,methyl, ethyl, n-propyl, isopropyl, —CH₂CF₃, —CH₂CHF2,—CH₂CH₂F,—CH₂CH₂OCH₃, cyclopropyl, cyclobutyl, tetrahydrofuranyl, phenyl,1-cyclopropylethyl, and 3-methylbutan-2-yl.

In some embodiments, each R^(a), is independently selected from H,methyl, 2-fluorophenyl, 3-(difluoromethoxy)pyridin-2-yl,2-cyanocyclopentyl, 2,6-dimethylpyridin-3-yl, 3-fluoropyridin-2-yl,4-(trifluoromethyl)pyridin-3-yl, 6-methoxy-2-methylpyridin-3-yl,3-fluoropyridin-4-yl, 4-methylpyridin-3-yl, 2-methylcyclobutyl,4-methoxyphenyl, 3-methylpyrazin-2-yl, 4-methoxypyridin-3-yl,tetrahydro-2H-pyran-3-yl, 2-methoxyphenyl, imidazo[1,2-a]pyridin-6-yl,(R)-tetrahydrofuran-3-yl, 2-cyanophenyl, and (2-cyanocyclopentypmethyl.

In some embodiments, each R^(a), is independently selected from methyl,ethyl, n-propyl, isopropyl, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F, —CH₂CH₂OCH₃,cyclopropyl, cyclobutyl, tetrahydrofuranyl, phenyl, 1-cyclopropylethyl,and 3-methylbutan-2-yl.

In some embodiments, R² is H, OH, OR^(a), NHR^(a), or NR^(a)R^(a).

In some embodiments, R² is H, OH, OR^(a), or NHR^(a).

In some embodiments, R² is H.

In some embodiments, R² is methoxy, 2,5-difluorophenoxy,2-fluorophenoxy, propylamino, isopropylamino, 2,2-difluoroamino,2-methoxyethylamino, hydroxyl, 2,2,2-trifluoroethylamino,cyclopropylamino, cyclopropylmethylamino, 3-methoxypropylamino,2,5-difluorophenylamino, cyclobutymethylamino, 3-fluorocyclobutylamino,methylamino, oxazol-4-ylmethylamino, 2-butylamino, cyanomethylamino,ethyl(methyl)amino, methyl(2-methoxyethyl)amino,2-fluoroethyl(methyl)amino, cyclopropyl(methyl)amino or dimethylamino.

In some embodiments, R³ is H, F, NH₂, —N(C₁₋₄ alkyl)₂ or —OC₁₋₆ alkyl.

In some embodiments, R³ is H or halo.

In some embodiments, R³ is H or F.

In some embodiments, R⁴ is H, F, NH₂, —N(C₁₋₄ alkyl)₂ or —OC₁₋₆ alkyl.

In some embodiments, R⁴ is H, F, NH₂, —N(CH₃)₂ or —C₁₋₄ alkoxy.

In some embodiments, R⁴ is H.

In some embodiments, R⁵ is H, F, NH₂, —N(CH₃)₂ or —C₁₋₄ alkoxy.

In some embodiments, R⁵ is H.

In some embodiments, R⁶ is H.

In some embodiments, X is N or CH.

In some embodiments, X is CR⁷.

In some embodiments, CR⁷ is CH.

In some embodiments, R⁷ is H or isopropylamino.

In some embodiments, X is N.

In some embodiments, R⁸ is H.

In some embodiments, the disclosure provides intermediates useful forthe synthesis of the compounds as described herein, wherein theintermediates have Formula (VII):

P¹ is an amino protecting group. R¹¹ is halo. The other variables R²,R³, R⁴, R⁵, R⁶, R⁷, X, m and n in Formula (VII) are as defined herein.

In some embodiments of compounds of Formula (VII), X is N or CR⁷,wherein R⁷ is H, halo, NH₂, C₁₋₄alkoxy, C₁₋₄alkyl-NH— or (C₁₋₄alkyl)₂N—;

R⁶ is H, halo, CN, OH, NH₂, NHCH₃, N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₂ haloalkyl, C₁₋₂ haloalkoxy, ethenyl, C₂₋₄alkynyl or C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, wherein C₁₋₄ alkyland C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroarylare each optionally substituted with OH, CN or CH₃O;

R¹¹ is halo;

R² is H, OH, ORP, NHR^(p) or NR^(p)R^(p), wherein each R^(p) isindependently selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5 or 6-membered heteroaryl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(p) are eachoptionally substituted with 1, 2 or 3 R^(r) substituents independentlyselected from OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₃₋₆cycloalkyl, NHR⁹, NR⁹R⁹, and C₁₋₄ haloalkoxy, wherein theC₁₋₄ alkyl of R^(r) is optionally substituted with OH, CN, NH₂, C₁₋₄alkoxy, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl and each R⁹is independently H or C₁₋₆ alkyl;

R³ is H, halo or CN;

R⁴ is H, halo, CN, OH, NH₂, NHCH₃, N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₂ haloalkyl, C₁₋₂ halaolkoxy, ethenyl, C₂₋₄alkynyl or cyclopropyl,wherein C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionally substituted withCN or CH₃O;

R⁵ is H, halo, CN, OH, NH₂, NHCH₃, N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄ alkoxy,C₁₋₂ haloalkyl, C₁₋₂haloalkoxy, ethenyl, C₂₋₄alkynyl or C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5 or 6-membered heteroaryl , wherein C₁₋₄ alkyl and C₁₋₄alkoxy are each optionally substituted with CN or CH₃O;

the subscript m is an integer of 1 or 2; and

the subscript n is an integer of 1, 2 or 3.

In some embodiments, the disclosure provides intermediates havingFormula (VIII):

wherein the variables R², R³, R⁴, R⁵, R⁶, R⁷, R¹¹, P¹, X, m and n inFormula (VII) are as defined herein.

In some embodiments of compounds of Formula (VII) or (VIII), P¹ ist-butoxycarbonyl. R² is H. R⁴ is H. R⁵ is H.

In some embodiments of compounds of Formula (VII) or (VIII), R⁶ ismethyl.

In some embodiments of compounds of Formula (VII) or (VIII), R³ is F.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds offormula (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring- forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)— includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chained orbranched. The term “C_(n-m)alkyl”, refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C-H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene”, employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, ethan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl,propan-1,1-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl,2-methyl-propan-1,3-diyl and the like.

The term “alkoxy”, employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

The term “amino” refers to a group of formula —NH₂.

The term “carbamyl” refers to a group of formula —C(O)NH₂.

The term “carbonyl”, employed alone or in combination with other terms,refers to a —C(═O)—group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula —C≡N, whichalso may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m)haloalkyl” refers to a C_(n-m)alkyl group having n to mcarbon atoms and from at least one up to {2(n to m)+1} halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments,the haloalkyl group is a fluoroalkyl group.

The term “haloalkoxy”, employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, and the like. In some embodiments, arylgroups have from 6 to about 10 carbon atoms. In some embodiments arylgroups have 6 carbon atoms. In some embodiments aryl groups have 10carbon atoms. In some embodiments, the aryl group is phenyl. In someembodiments, the aryl group is naphthyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3 or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-10 ring atomsincluding carbon atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl,quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-,1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine), indolyl,benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl,purinyl, imidazopyridinyl, and the like.

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term “cycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic hydrocarbon ring system (monocyclic,bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C₃₋₇).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally oxidized to form an oxo orsulfido group. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbomyl, norpinyl, norcarnyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic ring or ring system, which mayoptionally contain one or more alkenylene groups as part of the ringstructure, which has at least one heteroatom ring member independentlyselected from nitrogen, sulfur oxygen and phosphorus, and which has 4-10ring members, 4-7 ring members, or 4-6 ring members. Included within theterm “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-memberedheterocycloalkyl groups. Heterocycloalkyl groups can include mono- orbicyclic (e.g., having two fused or bridged rings) ring systems. In someembodiments, the heterocycloalkyl group is a monocyclic group having 1,2 or 3 heteroatoms independently selected from nitrogen, sulfur andoxygen. Ring- forming carbon atoms and heteroatoms of a heterocycloalkylgroup can be optionally oxidized to form an oxo or sulfido group orother oxidized linkage (e.g., C(O), S(O), C(S) or S(O)₂, N-oxide etc.)or a nitrogen atom can be quaternized. The heterocycloalkyl group can beattached through a ring-forming carbon atom or a ring-formingheteroatom. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 double bonds. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the heterocycloalkyl ring, e.g.,benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. Examples of heterocycloalkyl groups include azetidinyl,azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl,morpholino, 3-oxa-9-azaspiro[5.5]undecanyl,1-oxa-8-azaspiro[4.5]decanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl,2-oxo-5-azabicyclo[2.2.1]heptanyl, 6-oxo-3-azabicyclo[3.1.1]heptanyl,2.5-diazabicyclo[2.2.1]heptanyl, oxazepanyl, piperidinyl, piperazinyl,oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, indolinyl,tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl,4-oxodihydro-/H-pyrido[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl,2-azaspiro[3.3]heptanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl oxazinanyl,dihydro-1H-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl,dihydro-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl,2H-benzo[b][1,4]oxazin-4(3H)-yl, oxaazaspiro[3.5]nonanyl, diazepanyl,dihydro-1H-pyrazolo[3,4-c]pyridin-6 (7H, )-yl,dioxido-1,2,6-thiadiazinanyl,dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl,7-azabicyclo[2.2.1]heptanyl, dioxidoisothiazolidinyl, oxopyrrolidinyl,oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, oxodiazepanyl, tropanyl, andthiomorpholino.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as β-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of a-methylbenzylamine(e.g., S and R forms, or diastereomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone—enol pairs, amide—imidic acidpairs, lactam—lactim pairs, enamine—imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7 or 8deuterium atoms. Synthetic methods for including isotopes into organiccompounds are known in the art.

Substitution with heavier isotopes such as deuterium, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. (A. Kerekes et.al. J. Med.Chem. 2011, 54, 201-210; R. Xu et.al. J. Label Compd. Radiopharm. 2015,58, 308-312).

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The term “protecting group” refers to a grouping of atoms that whenattached to a reactive group in a molecule masks, reduces or preventsthat reactivity. Examples of protecting groups can be found in T. W.Greene and P. G. Wuts, Protective Groups in Organic Synthesis, (Wiley,4th ed. 2006), Beaucage and Iyer, Tetrahedron 48:2223-23 1 1(1992), andHarrison and Harrison et al, Compendium of Synthetic Organic Methods,Vols. 1-8 (John Wiley and Sons. 1971-1996). Representative aminoprotecting groups include formyl, acetyl, trifluoroacetyl, benzyl,benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethyl silyl(TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substitutedtrityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC),nitro-veratryloxycarbonyl (NVOC), tri-isopropylsilyl (TIPS),phenylsulphonyl and the like (see also, Boyle, A. L. (Editor),carbamates, amides, N-sulfonyl derivatives, groups of formula —C(O)OR,wherein R is, for example, methyl, ethyl, t-butyl, benzyl, phenylethyl,CH₂═CHCH₂—, and the like, groups of the formula —C(O)R′, wherein R′ is,for example, methyl, phenyl, trifluoromethyl, and the like, groups ofthe formula —SO₂R″, wherein R″ is, for example, tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl,2,3,6-trimethyl-4-methoxyphenyl, and the like, and silanyl containinggroups, such as 2-trimethylsilylethoxymethyl, t-butyldimethylsilyl,triisopropylsilyl, and the like.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J.Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

II. Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th)Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of formula (I) can be prepared, e.g., using a process asillustrated in Scheme 1. In the process depicted in Scheme 1, a suitablearomatic amine of formula 1-1 is reacted with an acid of formula 1-2under conditions suitable for forming an amide bond to provide thecompound of formula 1-3. Compounds of formula 1-1 can be prepared inaccordance with the protocols described in PCT publication WO2012/120428, which is incorporated herein by reference for all purposes.Suitable combinations for forming the amide bond include, e.g., themethods used to form amide bonds in peptides as described, e.g., inJones, Amino Acid and Peptide Synthesis, 2^(nd) Ed., Oxford UniversityPress, 2002; and Jones, The Chemical Synthesis of Peptides(International Series ofMonographs on Chemistry) (Oxford UniversityPress, 1994). An example of a suitable coupling agent is HATU/DIPEA. Thehalogen substituent in compounds of formula 1-3 can be converted into R¹via a number of different cross-coupling reactions, including Suzuki,Sonogashira, Negishi, BuchwaldHartwig amination and others, to give thedesired compounds of formula (I)

Compounds of formula 1-2 (or synthetic equivalents thereof) may beprepared, e.g., as shown in Scheme 2. Substituted bromo-quinolines ofgeneral formula 2-1 can be converted to the ester-quinolines of formula2-2 via palladium catalyzed carbonylation reaction. These compounds canbe further halogenated with one of the halogenated agents to formcompounds of formula 2-3. Finally, ester hydrolysis under basicconditions results in the formation of compounds of formula 1-2.

Starting materials, reagents and intermediates whose synthesis is notdescribed herein are either commercially available, known in theliterature, or may be prepared by methods known to one skilled in theart.

It will be appreciated by one skilled in the art that the processesdescribed are not the exclusive means by which compounds of theinvention may be synthesized and that a broad repertoire of syntheticorganic reactions is available to be potentially employed insynthesizing compounds of the invention. The person skilled in the artknows how to select and implement appropriate synthetic routes. Suitablesynthetic methods of starting materials, intermediates and products maybe identified by reference to the literature, including referencesources such as: Advances in Heterocyclic Chemistry, Vols. 1-107(Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49(Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.)Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge UpdatesKU2010/1-4; 2011-/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky, et al.(Ed.) Comprehensive Organic Functional Group Transformations, (PergamonPress, 1996); Katritzky et al. (Ed.); Comprehensive Organic FunctionalGroup Transformations II (Elsevier, 2^(nd) Edition, 2004); Katritzky etal. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984);Katritzky et al., Comprehensive Heterocyclic Chemistry II, (PergamonPress, 1996); Smith et al., March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley, 2007); Trost etal. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

III. Uses of the Compounds

Compounds of the invention can inhibit the activity of one or moremembers of the Pim kinase family and, thus, are useful in treatingdiseases and disorders associated with activity of Pim kinases. For theuses described herein, any of the compounds of the invention, includingany of the embodiments thereof, may be used.

The compounds of the invention can inhibit one or more of Pim1, Pim2 andPim3. In some embodiments the compounds are selective for one Pim kinaseover another. “Selective” means that the compound binds to or inhibits aPim kinase with greater affinity or potency, respectively, compared to areference enzyme, such as another Pim kinase. For example, the compoundscan be selective for Pim1over Pim2 and Pim3, selective for Pim2 overPim1and Pim3, or selective for Pim3 over Pim1and Pim2. In someembodiments, the compounds inhibit all of the Pim family members (e.g.,Pim1, Pim2 and Pim3). In some embodiments, the compounds can beselective for Pim over other kinases such as receptor and non-receptorSer/Thr kinases such as Akt1, Akt2, Akt3, TGF-PR, PKA, PKG, PKC,CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK and mTOR; receptor Tyrkinases such as EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR,PDGFβR, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2,FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4,EphA1, EphA2, EphA3, EphB2, EphB4, Tie2; and non-receptor Tyr kinasessuch as Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK or ABL. In general,selectivity can be at least about 5-fold, at least about 10-fold, atleast about 20-fold, at least about 50-fold, at least about 100-fold, atleast about 200-fold, at least about 500-fold or at least about1000-fold. The method of inhibiting a Pim1, Pim2 or Pim3 kinase includescontacting the appropriate enzyme with the compound of the invention, orany of the embodiments thereof, or a pharmaceutically acceptable saltthereof.

Thus, the present disclosure provides methods of treating a Pimkinase-associated disease or disorder in an individual (e.g., patient)by administering to the individual in need of such treatment atherapeutically effective amount or dose of a compound of the invention,or any of the embodiments thereof, or a pharmaceutical compositionthereof. The present disclosure also provides a compound of theinvention, or any of the embodiments thereof, or a pharmaceuticalcomposition thereof, for use in treating a Pim kinase-associated diseaseor disorder. Also provided is the use of a compound of the invention, orany of the embodiments thereof, or a pharmaceutical composition thereof,in the manufacture of a medicament for treating a Pim kinase-associateddisease or disorder.

A Pim kinase-associated disease can include any disease, disorder orcondition that is directly or indirectly linked to expression oractivity of the Pim kinase, including over- expression and/or abnormalactivity levels. Abnormal activity levels can be determined by comparingactivity level in normal, healthy tissue or cells with activity level indiseased cells. A Pim kinase-associated disease can also include anydisease, disorder or condition that can be prevented, ameliorated,inhibited or cured by modulating Pim kinase activity. In someembodiments, the disease is characterized by the abnormal activity orexpression (e.g., overexpression) of one or more Pim1, Pim2 and Pim3. Insome embodiments, the disease is characterized by mutant Pim1, Pim2 orPim3. A Pim kinase associated disease can also refer to any disease,disorder or condition wherein modulating the expression or activity ofone or more Pim kinases is beneficial.

Pim kinase associated diseases that can be treated using the compoundsof the invention include cancer, including, in particular, cancers inwhich Pim kinases are upregulated or an oncogene, e.g., Myc or Bcl2, isactivated. Pim kinase associated diseases include solid tumors, e.g.,prostate cancer, colon cancer, esophageal cancer, endometrial cancer,ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreaticcancer, gastric cancer, breast cancer, lung cancer, cancers of the heador neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc. Pimkinase associated diseases also include hematological cancers, e.g.,lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acutemyelogenous leukemia (A ML), chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (C ML), diffuse large B-cell lymphoma (DLBCL),mantle cell lymphoma, non-Hodgkin lymphoma (including relapsednon-Hodgkin lymphoma, refractory non-Hodgkin lymphoma and recurrentfollicular non-Hodgkin lymphoma), Hodgkin lymphoma and multiple myeloma.

Pim kinase associated diseases that can be treated using the compoundsof the invention also include myeloproliferative disorders such aspolycythemia vera (PV), essential thrombocythemia (ET), chronicmyelogenous leukemia (CML) and the like. The myeloproliferative disordercan be myelofibrosis such as primary myelofibrosis (PMF),post-polycythemia vera/essential thrombocythemia myelofibrosis(Post-PV/ET MF), post-essential thrombocythemia myelofibrosis (Post-ETMF) or post-polycythemia vera myelofibrosis (Post-PV MF).

Pim kinase-associated diseases that can be treated with compoundsaccording to the invention also include immune disorders such asautoimmune diseases. The immune disorders include multiple sclerosis,rheumatoid arthritis, allergy, food allergy, asthma, lupus, inflammatorybowel disease and ulcerative colitis.

Pim kinase-associated diseases that can be treated with compoundsaccording to the invention also include atherosclerosis.

The compounds of the invention can also be used to inhibit diseaseprocesses in which Pim-kinases are involved, including angiogenesis andtumor metastasis.

Due to the fact that Pim kinases are regulated by the JAK/STAT pathway,the compounds of the invention are useful to treat diseases in whichmodulating JAK/STAT signaling is beneficial. Thus, other diseases thatcan be treated using the compounds of the invention include Crohn'sdisease, irritable bowel syndrome, pancreatitis, diverticulosis, Grave'sdisease, juvenile rheumatoid arthritis, osteoarthritis, psoriaticarthritis, ankylosing spondylitis, myasthenia gravis, vasculitis,autoimmune thyroiditis, dermatitis, psoriasis, scleroderma, systemicsclerosis, vitiligo, graft versus host disease, Sjogren's syndrome,glomerulonephritis and diabetes mellitis (type I).

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred toherein; e.g., preventing or reducing the risk of developing adisease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine different kinase inhibitors,exhibiting different preferences in the kinases which they modulate theactivities of, to treat such conditions. Targeting more than onesignaling pathway (or more than one biological molecule involved in agiven signaling pathway) may reduce the likelihood of drug-resistancearising in a cell population, and/or reduce the toxicity of treatment.

Accordingly, the Pim inhibitors of the present invention can be used incombination with one or more other kinase inhibitors for the treatmentof diseases, such as cancer, that are impacted by multiple signalingpathways. For example, the compounds of the invention can be combinedwith one or more inhibitors of the following kinases for the treatmentof cancer: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM-kinase,phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4,INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR/FLK-1,FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB,TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2,Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-R^(a),f.Additionally, the Pim inhibitors of the invention can be combined withinhibitors of kinases associated with the PIK3/Akt/mTOR signalingpathway, such as PI3K, Akt (including Akt1, Akt2 and Akt3) and mTORkinases.

In some embodiments Pim inhibitors of the invention can be combined withinhibitors selective for JAK1 and/or JAK2 (e.g., ruxolitinib,baricitinib, momelotinib, filgotinib, pacritinib, INCB039110,INCB052793, INCB054707, CYT387, ABT494, AZD1-480, XL019, CEP-33779, AZ960, TG101209, and gandotinib). In some embodiments Pim inhibitors ofthe invention can be combined with inhibitors selective for JAK1 (e.g.INCB039110, INCB052793, INCB054707, and ABT494) such as those disclosedin e.g., WO 2010/135650, WO 2011/028685, WO 2011/112662, WO 2012/068450,WO 2012/068440, WO 2012/177606, WO 2013/036611, WO 2013/026025, WO2014/138168, WO 2013/173720, WO 2015/021153, WO 2014/071031, WO2014/106706, WO 2015/131031, WO 2015/168246, and WO 2015/184305. In someembodiments Pim inhibitors of the invention can be combined withinhibitors selective for JAK2 (e.g., pacritinib, AZD1480, XL019,CEP-33779, AZ 960, TG101209, and gandotinib).

In some embodiments Pim inhibitors of the invention can be combined withinhibitors selective for PI3K delta (e.g., idelalisib, INCB040093,INCB050465, and TGR 1202) such as those disclosed in e.g., WO2011/0008487, WO 2011/075643, WO 2011/075630, WO 2011/163195, WO2011/130342, WO 2012/087881, WO 2012/125629, WO 2012/135009, WO2013/033569, WO2013/151930, WO 2014/134426, WO 2015/191677, and WO2015/157257.

The Pim inhibitors of the present invention can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation or surgery. The compounds can be administeredin combination with one or more anti-cancer drugs, such as achemotherapeutics. Example chemotherapeutics include any of: abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab,bexarotene, bleomycin, bortezombi, bortezomib, busulfan intravenous,busulfan oral, calusterone, capecitabine, carboplatin, carmustine,cetuximab, chlorambucil, cisplatin, cladribine, clofarabine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparinsodium, dasatinib, daunorubicin, decitabine, denileukin, denileukindiftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat andzoledronate.

In some embodiments Pim inhibitors of the invention can be combined withcytarabine.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB, PD-1 and PD-L1, or antibodies to cytokines (IL-10, TGF-β,etc.).

The Pim inhibitors of the present invention can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies.

The Pim inhibitors of the present invention can be used in combinationwith one or more immune check point inhibitors. Exemplary immunecheckpoint inhibitors include inhibitors against immune checkpointmolecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR,CSF1R, JAK (e.g., JAK1 and/or JAK2), PI3K delta, PI3K gamma, TAM,arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H_(3,) B7-H4,BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2. In someembodiments, the immune checkpoint molecule is a stimulatory checkpointmolecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. Insome embodiments, the immune checkpoint molecule is an inhibitorycheckpoint molecule selected from A2AR, B7-H_(3,) B7-H4, BTLA, CTLA-4,IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In some embodiments, thecompounds provided herein can be used in combination with one or moreagents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors,CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.

In some embodiments, immune checkpoint inhibitors include inhibitorsagainst immune checkpoint molecules such as JAK1 and/or JAK2.

In some embodiments, immune checkpoint inhibitors include inhibitorsagainst immune checkpoint molecules such as CD96.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB001078C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016 or LAG525.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518 or MK-4166. In some embodiments, theanti-GITR antibody is INCAGN01876.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562. Insome embodiments, the OX40L fusion protein is MEDI6383. In someembodiments, the anti-OX40 antibody is INCAGN01949.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody.

In some embodiments Pim inhibitors of the invention can be combined withTIGIT inhibitors.

The Pim inhibitors of the present invention can be used in combinationwith one or more other anti-cancer agents including BET inhibitors(e.g., INCB054329, OTX015, and CPI-0610), LSD1 inhibitors (e.g.,GSK2979552 and INCB059872), HDAC inhibitors (e.g., panobinostat,vorinostat, and entinostat), DNA methyl transferase inhibitors (e.g.,azacitidine and decitabine), and other epigenetic modulators.

In some embodiments Pim inhibitors of the invention can be combined withBET inhibitors. In some embodiments Pim inhibitors of the invention canbe combined with LSD1 inhibitors. In some embodiments Pim inhibitors ofthe invention can be combined with HDAC inhibitors. In some embodimentsPim inhibitors of the invention can be combined with DNA methyltransferase inhibitors.

The Pim inhibitors of the present invention can be used in combinationwith one or more agents for the treatment of diseases such as cancer. Insome embodiments, the agent is an alkylating agent, a proteasomeinhibitor, a corticosteroid, or an immunomodulatory agent. Examples ofan alkylating agent include cyclophosphamide (CY), melphalan (MEL), andbendamustine. In some embodiments, the proteasome inhibitor iscarfilzomib. In some embodiments, the corticosteroid is dexamethasone(DEX). In some embodiments, the immunomodulatory agent is lenalidomide(LEN) or pomalidomide (POM).

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, sequentially, or in combination(e.g., for more than two agents).

IV. Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thus thepresent disclosure provides a composition comprising a compound Formula(I), or a pharmaceutically acceptable salt thereof, or any of theembodiments thereof, and at least one pharmaceutically acceptablecarrier. These compositions can be prepared in a manner well known inthe pharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is indicated and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier. In some embodiments, the composition comprises at least onecompound described herein, or a pharmaceutically acceptable saltthereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™) Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

V. Labeled Compounds and Assay Methods

The compounds of the invention can further be useful in investigationsof biological processes, including kinase signaling, in normal andabnormal tissues. Thus, another aspect of the present invention relatesto labeled compounds of the invention (radio-labeled,fluorescent-labeled, etc.) that would be useful not only in imagingtechniques but also in assays, both in vitro and in vivo, for localizingand quantitating Pim kinases in tissue samples, including human, and foridentifying Pim kinase ligands by inhibition binding of a labeledcompound. Accordingly, the present invention includes Pim kinase assaysthat contain such labeled compounds.

The present invention further includes isotopically-substitutedcompounds of the invention. An “isotopically-substituted” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). It is to be understood that a “radio-labeled” is acompound that has incorporated at least one isotope that is radioactive(e.g., radionuclide). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ³H(also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. Theradionuclide that is incorporated in the instant radio-labeled compoundswill depend on the specific application of that radio-labeled compound.For example, for in vitro Pim kinase labeling and competition assays,compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or willgenerally be most useful. For radio-imaging applications ^(11C), ¹⁸F,¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be mostuseful. In some embodiments the radionuclide is selected from the groupconsisting of ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. Synthetic methods forincorporating radio-isotopes into organic compounds are known in theart.

Specifically, a labeled compound of the invention can be used in ascreening assay to identify and/or evaluate compounds. For example, anewly synthesized or identified compound (i.e., test compound) which islabeled can be evaluated for its ability to bind a Pim-kinase bymonitoring its concentration variation when contacting with the Pimkinase, through tracking of the labeling. For example, a test compound(labeled) can be evaluated for its ability to reduce binding of anothercompound which is known to bind to a Pim kinase (i.e., standardcompound). Accordingly, the ability of a test compound to compete withthe standard compound for binding to the Pim kinase directly correlatesto its binding affinity. Conversely, in some other screening assays, thestandard compound is labeled and test compounds are unlabeled.Accordingly, the concentration of the labeled standard compound ismonitored in order to evaluate the competition between the standardcompound and the test compound, and the relative binding affinity of thetest compound is thus ascertained.

VI. Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of Pim kinase-associated diseases ordisorders, such as cancer, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of Formula (I), or any of the embodimentsthereof. Such kits can further include one or more of variousconventional pharmaceutical kit components, such as, e.g., containerswith one or more pharmaceutically acceptable carriers, additionalcontainers, etc., as will be readily apparent to those skilled in theart. Instructions, either as inserts or as labels, indicating quantitiesof the components to be administered, guidelines for administration,and/or guidelines for mixing the components, can also be included in thekit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to bePim-kinase inhibitors according to at least one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Open Access Preparative LCMS Purification of some of thecompounds prepared was performed on Waters mass directed fractionationsystems. The basic equipment setup, protocols and control software forthe operation of these systems have been described in detail inliterature. See, e.g., Blom, “Two-Pump At Column Dilution Configurationfor Preparative LC-MS”, K. Blom, J. Combi. Chem., 2002, 4, 295-301; Blomet al., “Optimizing Preparative LC-MS Configurations and Methods forParallel Synthesis Purification”, J. Combi. Chem., 2003, 5, 670-83; andBlom et al., “Preparative LC-MS Purification: Improved Compound SpecificMethod Optimization”, J. Combi. Chem., 2004, 6, 874-883.

Intermediate 1. tert-Butyl(1S,3R,5S)-3-(3-(5-fluoro-3-iodoquinoline-8-carboxamido)pyridin-4-yl)-5-methylcyclohexylcarbamate

Step 1. 5-Methyl-3-oxocyclohex-1-en-1-yl trifluoromethanesulfonate

To a solution of 5-methylcyclohexane-1,3-dione (50.1 g, 397 mmol) indichloromethane (DCM) (700 mL) was added sodium carbonate (46.3 g, 437mmol) and the resulting mixture was cooled to 0° C. A solution oftrifluoromethanesulfonic anhydride (66.8 mL, 397 mmol) in DCM (600 mL)was added to the reaction flask dropwise over 1 h at 0° C. The reactionmixture was stirred at room temperature for 2 h. The solution wasfiltered and the filtrate was quenched by careful addition of saturatedNaHCO₃ (aq) to reach pH=7. The organic layer was washed with water,brine, then dried over Na₂SO₄ and concentrated to give product as alight yellow oil which was used in the next step without purification.LCMS calculated for C₈F₁₀F₃O₄S (M+H)⁺: m/z=259.0; Found: 259.1.

Step 2.5-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one

A mixture of4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (77.6 g,306 mmol), potassium acetate (77.1 g, 785 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexedwith dichloromethane (1:1) (8.6 g, 10.0 mmol) under N₂ was combined witha solution of 5-methyl-3-oxocyclohex-1-en-1-yl trifluoromethanesulfonate(67.6 g, 262 mmol) in 1,4-dioxane (420 mL). The reaction mixture wasdegassed with nitrogen and stirred at 80° C. overnight. After cooling toroom temperature, the mixture was filtered through a pad of celite(eluted with EtOAc). The filtrate was concentrated in vacuo, and theresidue was used in next step without purification.

Step 3. 5-Methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-one

To a solution of5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one(20.0 g, 84.7 mmol) in 1,4-dioxane (120 mL) was added4-chloro-3-nitropyridine (10.0 g, 63.1 mmol), 2.0 M sodium carbonate inwater (63.1 mL, 126 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (2.58 g, 3.15 mmol). The mixture was refluxedunder nitrogen atmosphere for 1 h. The reaction mixture was diluted withethyl acetate and water, then filtered through a pad of celite, andwashed with EtOAc. The separatedaqueous layer was extracted with EtOAc(2×). The combined organic phases were washed with water, brine anddried over Na₂SO₄. The crude was purified by flash chromatography(eluting with a gradient 0-60% ethyl acetate in hexanes) to give thedesired product as an orange oil (6.6 g, 45%). LCMS calculated forC₁₂H₁₃N₂O₃ (M+H)⁺: m/z=233.1; Found: 233.1.

Step 4. cis-(+/−)-5-Methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-ol

To a solution of 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-one(6.6 g, 28 mmol) in ethanol (93 mL) was added cerium (III) chlorideheptahydrate (12.7 g, 34.1 mmol). The resulting mixture was cooled to 0°C. and sodium tetrahydroborate (1.29 g, 34.1 mmol) was addedportionwise. After stirring at 0° C. for 1 h, the reaction was quenchedwith water, concentrated to remove most of the ethanol. The residue wasextracted with ethyl acetate. The separated organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crude waspurified by flash chromatography (eluting with a gradient of 20-90%ethyl acetate in hexanes) to give the desired product as a racemicmixture (6.4 g, 96%). LCMS calculated for C₁₂H₁₅N₂O₃ (M+H)⁺: m/z=235.1;Found: 235.1.

Step 5.4-(3-(tert-Butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)-3-nitropyridine

A solution ofcis(+/−)-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-ol (6.4 g, 27mmol) in DMF (51 mL) was combined with 1H-imidazole (3.7 g, 55 mmol) andtert-butyldimethylsilyl chloride (5.8 g, 38 mmol). The mixture wasstirred at room temperature overnight. The reaction solution was dilutedwith water and extracted with ethyl acetate. The organic layer waswashed with water (2×), brine, dried over Na₂SO₄ and concentrated togive the crude product as an orange oil. LCMS calculated forC₁₈H₂₉N₂O₃Si (M+H)⁺: m/z=349.2; Found: 349.2.

Step 6.4-(3-(tert-Butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)pyridin-3-amine

The mixture of4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)-3-nitropyridine(9.3 g, 27 mmol), iron powder (8.9 g, 160 mmol) and acetic acid (67 mL)was stirred at room temperature for 2 h. The reaction mixture wasfiltered through a pad of Celite. The pad was rinsed with methanol. Thecombined filtrate was concentrated. The resulting residue was dissolvedin EtOAc, washed with saturated Na₂CO₃ (aq), and brine. The organiclayer was dried over Na₂SO₄, filtered and concentrated to give thedesired product as a yellow oil (7.7 g, 90%). LCMS calculated forC₁₈H₃₁N₂OSi (M+H)⁺: m/z=319.2; Found: 319.2.

Step 7.4-(3-(tert-Butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-amine

To a suspension of4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)pyridin-3-amine(7.7 g, 24 mmol) in methanol (203 mL) under N₂ was added 10% palladiumon carbon (2.64 g, 2.48 mmol). The mixture was purged with H₂ andstirred under H₂ balloon for 3 h. The mixture was filtered through a padof Celite which was further eluted with MeOH. The filtrate wasconcentrated to give the crude product as an off-white foamy solid (7.3g, 93%) which was used directly in the next step without furtherpurification. LCMS calculated for C₁₈H₃₃N₂OSi (M+H)⁺: m/z=321.2; Found:321.3.

Step 8. cis-(+/−)-Benzyl4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-ylcarbamate

To a solution of4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-amine(7.3 g, 23 mmol) in dichloromethane (DCM, 50 mL) was addedN-(benzyloxycarbonyloxy)succinimide (6.5 g, 26 mmol) and4-dimethylaminopyridine (0.14 g, 1.2 mmol). The mixture was stirred atroom temperature for 16 h. Then another portion ofN-(benzyloxycarbonyloxy)succinimide (3.1 g, 12 mmol) was added, followedby 4-dimethylaminopyridine. The reaction mixture was stirred foradditional 16 h. The reaction solution was partitioned between ethylacetate and sat. Na₂CO₃ (aq) solution. The separated organic layer waswashed with sat. Na₂CO₃ solution and brine, dried over Na₂SO₄, filteredand concentrated. The residue was purified by flash chromatography(eluting with a gradient of 0-40% ethyl acetate in hexanes) to give thedesired product as brown oil. LCMS calculated for C₂₆H₃₉N₂O₃Si (M+H)⁺:m/z=455.3; Found: 455.2.

Step 9. cis-(+/−)-Benzyl 4-(3-hydroxy-5-methylcyclohexyl)pyridin-3-ylcarbamate

To a solution of cis (+/−) benzyl4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-ylcarbamate (7.0 g, 15 mmol) in methanol (100 mL) was added 6.0 M hydrogenchloride in water (50.0 mL, 300. mmol). The resulting mixture wasstirred at room temperature for 6 h. The pH was then adjusted to pH=7 byaddition of 6 N NaOH and the volatiles were removed in vacuo. Theresulting aqueous was extracted with EtOAc and the organic was washedwith brine, dried over MgSO₄, filtered and concentrated to give thecrude product which was used in next step without further purification(4.8 g, 92%). LCMS calculated for C₂₀H₂₅N₂O₃ (M+H)⁺: m/z=341.2; Found:341.1.

Step 10. cis-(+/−)-Benzyl4-(3-methyl-5-oxocyclohexyl)pyridin-3-ylcarbamate

A solution of cis-(+/−)-benzyl4-(3-hydroxy-5-methylcyclohexyl)pyridin-3-yl carbamate (4.8 g, 14 mmol)in DCM (90. mL) was added Dess-Martin periodinane (8.97 g, 21.2 mmol).The reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was diluted with ether and saturated NaHCO₃ (aq)solution and stirred for 30 min. The organic layer was separated andwashed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude was purified with flash chromatography (eluting with a gradient of0-50% ethyl acetate in hexanes) to give the desired product (2.5 g,52%). LCMS calculated for C₂₀H₂₃N₂O₃ (M+H)⁺: m/z=339.2; Found: 339.1.

Step 11. cis-(+/−)-Benzyl4-(3-(benzylamino)-5-methylcyclohexyl)pyridin-3-ylcarbamate

To a solution of cis-(+/−)-benzyl4-(3-methyl-5-oxocyclohexyl)pyridin-3-ylcarbamate (2.50 g, 7.39 mmol) inmethanol (30. mL) was added benzylamine (2.42 mL, 22.2 mmol). Theresulting mixture was stirred at room temperature for 2 h. After coolingto −78° C., the reaction was treated with 2.0 M lithium tetrahydroboratein THF (4.1 mL, 8.1 mmol). The mixture was allowed to warm to roomtemperature and stirred overnight. The solution was partitioned betweenEtOAc and sat. NaHCO₃ (aq). The organic layer wasseparated, washedfurther with sat. NaHCO₃ (aq) and brine, dried over MgSO₄, filtered andconcentrated. The crude was used in the next step without furtherpurification (3.1 g, 98%). LCMS calculated for C₂₇H₃₂N₃O₂ (M+H)⁺:m/z=430.2; Found: 430.2.

Step 12. tert-Butyl[(1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl]carbamate (Peak2) and tert-Butyl[(1R,3S,5R)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl]carbamate (Peak1)

To a solution of cis-(+/−)-benzyl4-(3-(benzylamino)-5-methylcyclohexyl)pyridin-3-ylcarbamate (3.10 g,7.22 mmol) in methanol (100 mL) was added 20% palladium hydroxide (1.0g, 1.4 mmol). The resultant heterogeneous solution was put under anatmosphere of hydrogen and was stirred for 14 h. At this time thereaction was purged with N₂, then di-tert-butyldicarbonate (1.6 g, 7.2mmol) was added and the solution was stirred for 7 h. Additionaldi-tert-butyldicarbonate (1.6 g, 7.2 mmol) was added and the solutionwas stirred overnight. The solvent was removed in vacuo and the residuewas purified with flash chromatography (eluting with a gradient of20-100% ethyl acetate in hexanes) to give the racemic product. Theracemic mixture was separated by chiral column (CHIRALPAK IA Col, 15%ethanol/85% hexanes, 12 mL/min) to give two peaks. Peak 1: RT 8.2-9.5min; Peak 2: RT 10.6-12.4 min. LCMS calculated for C₁₇H₂₈N₃O₂ (M+H)⁺:m/z=306.2; Found: 306.2.

Step 13. Methyl 5-fltioroquinoline-8-carboxylate

A mixture of 8-bromo-5-fluoroquinoline (6.0 g, 26 mmol, Combi-Blocks)and [1,1′-bis(diphenylphosphino)ferroceneldichloropalladium(II)complexed with dichloromethane (1:1) (2.2 g, 2.6 mmol, Combi-Blocks) wasplaced in a flask with a septum. The flask was then evacuated andbackfilled with nitrogen three times. After addition of methanol (100mL) and triethylamine (7.4 mL, 53 mmol) the flask was evacuated andbackfilled with carbon monoxide gas three times. Then a balloon withcarbon monoxide gas was connected to the reaction flask and reactionmixture was heated at 85° C. overnight. After cooling down to r.t., thereaction mixture was filtered through Celite and concentrated underreduced pressure. Crude material was purified by Biotage Isolera™ (flashpurification system with hexane/ethyl acetate at a ratio from 0 to 100%)to give the desired product (4.64 g, 87%). LCMS calculated for C₁₁H₉FNO₂(M+H)⁺ m/z=206.1; found: 206.0.

Step 1-4. Methyl 5-fltioro-3-iodoquinoline-8-carboxylate

N-Iodosuccinimide (3.0 g, 13 mmol) was slowly added to a solution of5-fluoroquinoline-8-carboxylate (1.3 g, 6.3 mmol) in acetic acid (8.0mL) at r.t. After stirring at 50° C. overnight, the reaction wasconcentrated at reduced pressure and crude product was redissolved inethyl acetate. Then pH was adjusted to 8 by the addition of saturatedsolution of sodium bicarbonate. The product was extracted with ethylacetate. The organic phase was washed with brine and saturated solutionof sodium thiosulfate, dried over sodium sulfate and solvent wasevaporated under reduced pressure. Crude material was purified byBiotage Isolera™ (flash purification system with hexane/ethyl acetate ata ratio from 0 to 100%) to give the desired compound (1.92 g, 92%). LCMScalculated for C₁₁H₈FINO₂ (M+H)⁺ m/z=332.0; found: 332.0.

Step 15. 5-Fluoro-3-iodoquinoline-8-carboxylic acid

A 1 M solution of sodium hydroxide in water (10 mL, 10 mmol) was addedto a solution of methyl 5-fluoro-3-iodoquinoline-8-carboxylate (1.5 g,4.5 mmol) in tetrahydrofuran (10 mL) and methanol (6 mL). After stirringat r.t. for 2 h, pH was adjusted to 5 by the addition of a 1 M solutionof HCl. The product was then extracted with ethyl acetate and theorganic phase was washed with brine. The organic phase was dried oversodium sulfate and the solvent was evaporated under reduced pressure.The obtained solid product was used in the next step without furtherpurification (1.35 g, 95%). LCMS calculated for C₁₀H₆FINO₂ (M+H)⁺m/z=317.9; found 317.9.

Step 16. tert-Butyl(1S,3R,5S)-3-(3-(5-fluoro-3-iodoquinoline-8-carboxamido)pyridin-4-yl)-5-methylcyclohexylcarbamate

To a solution of tert-butyl(1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexylcarbamate (400 mg,1.3 mmol; Peak 2 of Step 12) and 5-fluoro-3-iodoquinoline-8-carboxylicacid (494 mg, 1.56 mmol) in N,N-dimethylformamide (10 mL) were addedN,N-diisopropylethylamine (480 μL, 2.7 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (780 mg, 2.1 mmol). After the reaction mixture wasstirred at r.t. for 2 hours, it was quenched by the addition of water.The precipitate was collected by filtration and washed with water twice.Then it was redissolved in ethyl acetate to give a solution which waswashed with brine and dried over sodium sulfate. After the solvent wasevaporated, the crude product was purified by Biotage Isolera™ (flashpurification system with hexane/ethyl acetate at a ratio from 0 to 100%)to give the desired compound (595 mg, 76%). LCMS calculated forC₂₇H₃₁FIN₄O₃ (M+H)⁺ m/z=605.1; found 605.1.

Intermediate 2. tert-Butyl[(1S,3R,5S)-3-(3-{[(3-bromoquinolin-8-yl)carbonyl]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate

To a solution of tert-butyl(1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexylcarbamate (200 mg,0.65 mmol) and 3-bromoquinoline-8-carboxylic acid (200 mg, 0.79 mmol) inN,N-dimethylformamide (5 mL) were added N,N-diisopropylethylamine (240μL, 1.35 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (390 mg, 1.05 mmol). After the reaction mixture wasstirred at r.t. for 2 hours, it was quenched by the addition of water.The precipitate was collected by filtration and washed with water twice.Then it was redissolved in ethyl acetate to give a solution which waswashed with brine and dried over sodium sulfate. After the solvent wasevaporated, the crude product was purified by Biotage Isolera™ (flashpurification system with hexane/ethyl acetate at a ratio from 0 to 100%)to give the desired compound (290 mg, 83%). LCMS calculated forC₂₇H₃₂BrN₄O₃ (M+H)⁺ m/z=539.2; found 539.1.

Example 1N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-ethyl-5-fluoroquinoline-8-carboxamide

Step 1. Methyl 5-fluoroquinoline-8-carboxylate

A mixture of 8-bromo-5-fluoroquinoline (8.00 g, 35.4 mmol) (fromCombi-Block), [1,1-bis(diphenylphosphino)ferroceneldichloropalladium(II)complexed with dichloromethane (1:1) (2.9 g, 3.5 mmol) and triethylamine(9.9 mL, 71 mmol) in methanol (100 mL) was degassed, bubbled with CO for1 minute, and refluxed under a balloon of CO for 2 h. The reactionmixture was filtered through a pad of Celite which was further rinsedwith EtOAc. The filtrate was concentrated and the residue was purifiedby flash chromatography (eluting with a gradient of 0-50% EtOAc inhexanes) to give the desired product as a brown oil (7.0 g, 96%). LCMScalculated for C₁₁H₉FNO₂ (M+H)⁺: m/z=206.1; Found: 206.1. C₁₁H₈FNO₂.

Step 2. Methyl 3-bromo-5-fluoroquinoline-8-carboxylate

To a mixture of methyl 5-fluoroquinoline-8-carboxylate (11.0 g, 53.6mmol) in acetic acid (60 mL) was added N-bromosuccinimide (10.0 g, 56.3mmol). The reaction was stirred at room temperature for 1 h. The solventwas removed in vacuo, and the residue was diluted with ethyl acetate andsaturated NaHCO₃ solution. The separated aqueous layer was extractedwith EtOAc (2×) and the combined organic phases were washed with water,brine , dried over Na₂SO₄ and filtered. The filtrate was concentratedunder reduced pressure, and the residue was purified by flashchromatography (eluting with a gradient of 0-30% EtOAc in hexanes) togive the desired product white solid (4.3 g, 28%). LCMS calculated forC₁₁H₈BrFNO₂ (M+H)⁺: m/z=284.0, 286.0; Found: 284.0, 286.0.

Step 3. 3-Bromo-5-fluoroquinoline-8-carboxylic acid

A mixture of methyl 3-bromo-5-fluoroquinoline-8-carboxylate (450 mg, 1.6mmol), THF (9 mL) and 1.0 M sodium hydroxide in water (9.5 mL, 9.5 mmol)was stirred at room temperature for 1 h. The pH of the solution wasadjusted to 3 with 1 M solution of HCl (aq). The aqueous layer wasextracted with ethyl acetate (2×). The organic layers were dried overNa₂SO₄, filtered and concentrated to give the desired product as a whitesolid (410 mg, 96%). LCMS calculated for C₁₀H₆BrFNO₂ (M+H)⁺: m/z=270.0,272.0; Found: 270.0, 272.0.

Step 4. tert-Butyl[(1S,3R,5S)-3-(3-{[(3-bromo-5-fluoroquinolin-8-yl)carbonyl]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate

To a solution of 3-bromo-5-fluoroquinoline-8-carboxylic acid (196 mg,0.726 mmol) and tert-butyl[(1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl]carbamate (185mg, 0.605 mmol, Intermediate 1, Step 12) in DMF (1 mL) were addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (335 mg, 0.880 mmol) and N,N-diisopropylethylamine(320 μL, 1.8 mmol). The reaction mixture was stirred at room temperatureovernight. The reaction mixture was diluted with DCM and water, and theseparated aqueous layer was extracted with DCM once. The combinedorganic layers were washed with water, brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified with flashchromatography (eluting with a gradient of 0-100% EtOAc in hexanes) togive the desired product as a white solid (285 mg, 85%). LCMS calculatedfor C₂₇H₃₁BrFN₄O₃ (M+H)⁺: m/z=557.2, 559.2; Found: 557.1, 559.1.

Step 5. tert-Butyl[(1S,3R,5S)-3-(3-{[(5-fluoro-3-vinylquinolin-8-yl)carbony]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate

A microwave vial was charged with tert-butyl[(1S,3R,5S)-3-(3-{[(3-bromo-5-fluoroquinolin-8-yl)carbonyl]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate(27.8 mg, 0.0499 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (3.4 mg, 0.0044 mmol) and tripotassium phosphate hydrate (25.3 mg,0.110 mmol). The vial was sealed and evacuated under high vacuum andbackfilled with nitrogen (repeated three times). 1,4-Dioxane (0.54 mL)and water (0.18 mL) were added, followed by4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (12.3 mg, 0.0798 mmol).The mixture was stirred at 70° C. for 1 h. After cooling to roomtemperature, the mixture was diluted with water and DCM. The organiclayer was concentrated and purified with flash chromatography (elutingwith a gradient of 0-100% EtOAc in hexanes) to give the desired productas a yellow oil (13 mg, 52%). LCMS calculated for C₂₉H₃₄FN₄O₃ (M+H)⁺:m/z=505.3; Found: 505.3.

Step 6.N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-ethyl-5-fluoroquinoline-8-carboxamide

To a solution of tert-butyl[(1S,3R,5S)-3-(3-{[(5-fluoro-3-vinylquinolin-8-yl)carbonyl]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate(13 mg, 0.026 mmol) in methanol (1 mL) was added 10% palladium on carbon(3 mg). The resulting mixture was stirred under H₂ balloon for 2 h. Themixture was filtered and the filtrate was concentrated. The residue wastreated with 1:1 DCM/TFA (2 mL) for 1 h. The volatiles were removed invacuo and the residue was dissolved in methanol and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of60 mL/min) to give the desired product as white solid (6.5 mg, 50%).LCMS calculated for C₂₄H₂₈FN₄O (M+H)⁺: m/z=407.2; Found: 407.2.

Example 2N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(3,R)-3-fluoropiperidin-1-yl]quinoline-8-carboxamide

Step 1. tert-Butyl((1S,3R,5S)-3-{3-[({5-fluoro-3-[(3R)-3-fluoropiperidin-1-yl]quinolin-8-yl}carbonyl)amina]pyridin-4-yl}-5-methylcyclohexyl)carbamate

A vial was charged with tert-butyl[(1S,3R,5S)-3-(3-{[(3-bromo-5-fluoroquinolin-8-yl)carbonyl]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate(30.0 mg, 0.0538 mmol), (3R)-3-fluoropiperidine hydrochloride (16.5 mg,0.118 mmol),dicyclohexyl-(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (6.3 mg, 0.0081 mmol) and cesium carbonate (71.9 mg, 0.221 mmol).The vial was sealed with a teflon screw-cap, evacuated and backfilledwith nitrogen (this process was repeated a total of three times).Anhydrous tert-butyl alcohol (0.4 mL) was added. The mixture was heatedto 90° C. for 5 h. The reaction mixture was diluted with water and DCM,the organic layer was separated and concentrated. The crude was purifiedwith flash chromatography (eluting with a gradient of 0-100% ethylacetate in hexanes) to give the desired product as yellow foam. LCMScalculated for C₃₂H₄₀F₂N₅O₃ (M+H)⁺: m/z=580.3; Found: 580.3.

Step 2.N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(3R)-3-fluoropiperidin-1-yl]quinoline-8-carboxamide

The product from above step was treated with 1:1 DCM/TFA (2 mL) for 1 h.The volatile was removed in vacuo and the residue was dissolved inmethanol and purified with purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) to give the desired product asyellow solid (6.6 mg, 26% two steps). LCMS calculated for C₂₇H₃₂F₂N₅O(M+H)⁺: m/z=480.3; Found: 480.2. ¹H NMR (600 MHz, DMSO-d₆) δ 13.10 (d,J=3.9 Hz, 1H), 9.24 (d, J=7.8 Hz, 1H), 9.06 (m, 1H), 8.54 (d, J=5.4 Hz,1H), 8.43 (dd, J=8.3, 6.2 Hz, 1H), 8.02 (s, 2H), 7.76 (d, J=3.0 Hz, 1H),7.59 (m, 1H), 7.54 (m, 1H), 4.95 (m, 1H), 3.85 (m,1H), 3.72-3.57 (m,2H), 3.40-3.33 (m, 1H), 3.26-3.19 (m, 2H), 2.13 (m, 1H), 1.99 (m, 2H),1.92 (m, 3H), 1.74 (m, 1H), 1.67 (m, 1H), 1.55 (q, J=12.0 Hz, 1H), 1.14(m, 1H), 1.08 (m, 1H),1.00 (t, J=6.4 Hz, 3H) ppm.

Example 3N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-pyrrolidin-1-ylquinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using pyrrolidine instead of (3R)-3-fluoropiperidinehydrochloride as starting material. LCMS calculated for C₂₆H₃₁FN₅O(M+H)⁺: m/z=448.2; Found: 448.3.

Example 4N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-azetidin-1-yl-5-fluoroquinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using azetidine instead of (3R)-3-fluoropiperidinehydrochloride as starting material. LCMS calculated for C₂₅H₂₉FN₅O(M+H)⁺: m/z=434.2; Found: 434.3.

Example 5N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(3S)-3-fluoropyrrolidin-1-yl]quinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using (3S)-3-fluoropyrrolidine hydrochloride instead of(3R)-3-fluoropiperidine hydrochloride as starting material. LCMScalculated for C₂₆H₃₀F₂N₅O (M+H)⁺: m/z=466.2; Found: 466.3.

Example 6N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(3R)-3-fluoropyrrolidin-1-yl]quinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using (3R)-3-fluoropyrrolidine hydrochloride instead of(3R)-3-fluoropiperidine hydrochloride as starting material. LCMScalculated for C₂₆H₃₀F₂N₅O (M+H)⁺: m/z=466.2; Found: 466.3.

Example 7N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-[(3S)-3-cyanopyrrolidin-1-yl]-5-fluoroquinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using (3S)-pyrrolidine-3-carbonitrile hydrochloride insteadof (3R)-3-fluoropiperidine hydrochloride as starting material. LCMScalculated for C₂₇H₃₀FN₆O (M+H)⁺: m/z=473.2; Found: 473.3.

Example 8N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-[(3R)-3-cyanopyrrolidin-1-yl]-5-fluoroquinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using (3R)-pyrrolidine-3-carbonitrile hydrochloride insteadof (3R)-3-fluoropiperidine hydrochloride as starting material. LCMScalculated for C₂₇H₃₀FN₆O (M+H)⁺: m/z=473.2; Found: 473.3.

Example 9N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-(3-fluoroazetidin-1-yl)quinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using 3-fluoroazetidine hydrochloride instead of(3R)-3-fluoropiperidine hydrochloride as starting material. LCMScalculated for C₂₅H₂₈F₂N₅O (M+H)⁺: m/z=452.2; Found: 452.3.

Example 10N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-morpholin-4-ylquinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using morpholine instead of (3R)-3-fluoropiperidinehydrochloride as starting material. LCMS calculated for C₂₆H₃₁FN₅O₂(M+H)⁺: m/z=464.2; Found: 464.3.

Example 11N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(38)-3-methoxypiperidin-1-yl]quinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using (35)-3-methoxypiperidine hydrochloride instead of(3R)-3-fluoropiperidine hydrochloride as starting material. LCMScalculated for C₂₈H₃₅FN₅O₂ (M+H)⁺: m/z=492.3; Found: 492.3.

Example 12N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(3S)-3-methoxypiperidin-1-yl]quinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using (3R)-3-methoxypiperidine hydrochloride instead of(3R)-3-fluoropiperidine hydrochloride as starting material. LCMScalculated for C₂₈H₃₅FN₅O₂ (M+H)⁺: m/z=492.3; Found: 492.3.

Example 13N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-cyclopropyl-5-fluoroquinoline-8-carboxamide

Step 1. tert-Butyl[(1S,3R,5S)-3-(3-{[(3-cyclopropyl-5-fluoroquinolin-8-yl)carbonyl]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate

To a microwave vial was added tert-butyl[(1S,3R,5S)-3-(3-{[(3-bromo-5-fluoroquinolin-8-yl)carbonyl]amino}pyridin-4-yl-5-methylcyclohexyl]carbamate(30.3 mg, 0.0544 mmol), potassium cyclopropyltrifluoroborate (9.6 mg,0.065 mmol), cesium carbonate (53.1 mg, 0.163 mmol), palladium acetate(1.2 mg, 0.0054 mmol) and di-1-adamantyl(butyl)phosphine (2.9 mg, 0.0082mmol). The vial was seal and evacuated then backfilled with N₂ (thisprocedure was repeated three times), then toluene (0.25 mL) and water(0.025 mL) were added. The reaction mixture was heated at 100° C. for 16h. After cooling to room temperature, the reaction mixture was dilutedwith water and ethyl acetate. The aqueous layer was extracted with ethylacetate once. The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The residue was purified with flashchromatography (eluting with a gradient of 0-100% ethyl acetate inhexanes) to give the desired product as yellow foam. LCMS calculated forC₃₀H₃₆FN₄O₃ (M+H)⁺: m/z=519.3; Found: 519.2.

Step 2.N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-cyclopropyl-5-fluoroquinoline-8-carboxamide

The product from the previous step was treated with 1:1 DCM/TFA (2 mL)for 1 h. The volatiles waere removed in vacuo and the residue wasdissolved in methanol and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) to give the desired product as awhite solid (8.6 mg, 38% for two steps). LCMS calculated for C₂₅H₂₈FN₄O(M+H)⁺: m/z=419.2; Found: 419.2.

Example 1-4N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(cyclopropylethynyl)-5-fluoroquinoline-8-carboxamide

Step 1. tert-Butyl{(1S,3R,5S)-3-[3-({[3-(cyclopropylethynyl)-5-fluoroquinolin-8-yl]carbonyl}amino)pyridin-4-yl]-5-methylcyclohexyl}carbamate

A microwave vial was charged with tert-butyl[(1S,3R,5S)-3-(3-{[(3-bromo-5-fluoroquinolin-8-yl)carbonyl]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate(32.5 mg, 0.0583 mmol), copper(I) iodide (1.38 mg, 0.00723 mmol) anddichloro[bis(triphenylphosphonio)]palladium (3.37 mg, 0.00481 mmol). Thevial was sealed and evacuated then backfilled with N₂ (this procedurewas repeated three times), then DMF (0.50 mL) and triethylamine (24.4μL, 0.175 mmol) were added, followed by ethynylcyclopropane (1-4.8 μL,0.175 mmol). The reaction mixture was stirred at 60° C. for 3 h. Aftercooling to rt, the reaction mixture was quenched with water and aqueouslayer was extracted with EtOAc, the organic layer was washed with brine,dried over Na₂SO₄, and filtered. The filtrate was concentrated in vacuoand the residue was purified with flash chromatography (eluting with agradient of 0-100% ethyl acetate in hexanes) to give the desired productas a yellow foam. LCMS calculated for C₃₂H₃₆FN₄O₃ (M+H)⁺: m/z=543.3;Found: 543.2.

Step 2.N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(cyclopropylethynyl)-5-fluoroquinoline-8-carboxamidetris(trifluoroacetate)

The product from the previous step was treated with 1:1 DCM/TFA (2 mL)for 1 h. The volatiles were removed in vacuo and the residue wasdissolved in methanol and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.05% TFA, atflow rate of 60 mL/min) to give the desired product as a TFA salt (whitesolid, 12.5 mg, 27% for two steps). LCMS calculated for C₂₇H₂₈FN₄O(M+H)⁺: m/z=443.2; Found: 443.1.

Example 15N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(2-cyano-6-fluorophenyl)-5-fluoroquinoline-8-carboxamide

Step 1. tert-Butyl((1S,3R,5S)-3-{3-[({3-[2-(aminocarbonyl)-6-fluorophenyl]-5-fluoroquinolin-8-yl}carbonyl)amino]pyridin-4-yl}-5-methylcyclohexyl)carbamate

To a microwave vial was added tert-butyl[(1S,3R,5S)-3-(3-{[(3-bromo-5-fluoroquinolin-8-yl)carbonyl]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate(33.4 mg, 0.0599 mmol), (2-cyano-6-fluorophenyl)boronic acid (15.8 mg,0.0958 mmol),dicyclohexyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (3.4 mg, 0.0044 mmol) and tripotassium phosphate hydrate (25.3 mg,0.110 mmol). The vial was sealed and evacuated under high vacuum andbackfilled with nitrogen (repeated three times). 1,4-Dioxane (0.54 mL)and water (0.18 mL) were added. The mixture was stirred at 70° C. for 1h. After cooling to room temperature, the mixture was diluted with waterand DCM. The organic layer was concentrated and purified with flashchromatography (eluting with a gradient of 0-100% EtOAc in hexanes) togive the desired product as a yellow oil (26 mg, 70%). LCMS calculatedfor C₃₄H₃₆F₂N₅O₄ (M+H)⁺: m/z=616.3; Found: 616.3.

Step 2.N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(2-cyano-6-fluorophenyl)-5-fluoroquinoline-8-carboxamide

To a solution of tert-butyl((1S,3R,5S)-3-{3-[({3-[2-(aminocarbonyl)-6-fluorophenyl]-5-fluoroquinolin-}carbonyl)amino]pyridin-4-yl}-5-methylcyclohexyl)carbamate (26 mg, 0.042 mmol) in DCM (1 mL) was addedtrichloroacetyl chloride (13 μl, 0.12 mmol) and pyridine (14.5 μl, 0.18mmol). After stirring at room temperature for 2 h, the volatiles wereremoved in vacuo. The residue was treated with 1:1 DCM/TFA (2 mL) for 1h. The volatiles were removed in vacuo and the residue was dissolved inmethanol and purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) to give the desired product as a white solid (16mg, 46%). LCMS calculated for C₂₉H₂₆F₂N₅O (M+H)⁺: m/z=498.2; Found:498.1. ¹H NMR (600 MHz, DMSO-d6) δ 12.57 (s, 1H), 9.37 (m, 1H), 9.08 (m,2H), 8.81 (dd, J=8.4, 6.3 Hz, 1H), 8.39 (d, J=5.1 Hz, 1H), 8.01 (dd,J=7.7, 1.0 Hz, 1H), 7.89 (m, 1H), 7.81 (m, 2H), 7.38 (d, J=5.1 Hz, 1H),3.16 (m 1H), 2.95 (m, 1H), 2.04 (d, J=11.9 Hz, 1H), 1.84 (m, 2H), 1.67(m, 1H), 1.30 (q, J=12.0 Hz, 1H), 1.12 (q, J=12.1 Hz, 1H), 1.00 (d,J=6.3 Hz, 3H), 0.92 (m, 1H) ppm.

Example 16 tert-Butyl{(1S,3R,5S)-3-[3-({[3-(2,6-difluorophenyl)-5-fluoroquinolin-8-yl]carbonyl}amino)pyridin-4-yl]-5-methylcyclohexyl}carbamate

Step 1. tert-Butyl{(1S,3R,5S)-3-[3-({[3-(2,6-difluorophenyl)-5-fluoroquinolin-8-yl]carbonyl}amino)pyridin-4-yl]-5-methylcyclohexyl}carbamate

This compound was prepared according to the procedure described inExample 1, Step 5, using2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane insteadof 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane as starting material.LCMS calculated for C₃₃H₃₄F₃N₄O₃ (M+H)⁺: m/z=591.3; Found: 591.3.

Step 2. tert-Butyl{(1S,3R,5S)-3-[3-({[3-(2,6-difluorophenyl)-5-fluoroquinolin-8-yl]carbonyl}amino)pyridin-4-yl]-5-methylcyclohexyl}carbamate

The product from the previous step was treated with 1:1 DCM/TFA (2 mL)for 1 h.

The volatiles were removed in vacuo and the residue was dissolved inmethanol and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% ammonium hydroxide, atflow rate of 60 mL/min) to give the desired product as a white solid.LCMS calculated for C₂₈H₂₆F₃F₄O (M+H)⁺: m/z=491.2; Found: 491.2.

Example 17N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(2-cyanophenyl)-5-fluoroquinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 16, using (2-cyanophenyl)boronic acid instead of2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane asstarting material. LCMS calculated for C₂₉H₂₇FN₅O (M+H)⁺: m/z=480.2;Found: 480.2.

Example 18N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(2,6-difluoro-4-hydroxyphenyl)-5-fluoroquinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 16, using (2,6-difluoro-4-hydroxyphenyl)boronic acid instead of2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane asstarting material. LCMS calculated for C₂₈H₂₆F₃N₄O₂ (M+H)⁺: m/z=507.2;Found: 507.2.

Example 19N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-[(cyclopropylmethyl)(methyl)amino]-5-fluoroquinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using 1-cyclopropyl-N-methylmethanamine hydrochloride insteadof (3R)-3-fluoropiperidine hydrochloride as starting material. LCMScalculated for C₂₇H₃₃FN₅O (M+H)⁺: m/z=462.3; Found: 462.3.

Example 20N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(ethyl(methyl)amino)-5-fluoroquinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using N-methyl-ethanamine, instead of (3R)-3-fluoropiperidinehydrochloride as starting material. LCMS calculated for C₂₅H₃₁FN₅O(M+H)⁺: m/z=436.2; Found: 436.2.

Example 21N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[methyl(2,2,2-trifluoroethypamino]quinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using 2,2,2-trifluoro-N-methylethanamine hydrochloride,instead of (3R)-3-fluoropiperidine hydrochloride as starting material.LCMS calculated for C₂₅H₂₈F₄N₅O (M+H)⁺: m/z=490.2; Found: 490.2.

Example 22N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(2-fluoroethyl)(methyl)amino]quinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using 2-fluoro-N-methylethanamine hydrochloride, instead of(3R)-3-fluoropiperidine hydrochloride as starting material. LCMScalculated for C₂₅H₃₀F₂N₅O (M+H)⁺: m/z=454.2; Found: 454.3.

Example 23N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[methybtetrahydrofuran-3-yl)amino]quinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using N-methyltetrahydrofuran-3-amine, instead of(3R)-3-fluoropiperidine hydrochloride as starting material. LCMScalculated for C₂₇H₃₃FN₅O₂ (M+H)⁺: m/z=478.3; Found: 478.3.

Example 24N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-[cyclobutybmethyl)amino]-5-fluoroquinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using N-methylcyclobutanamine, instead of(3R)-3-fluoropiperidine hydrochloride as starting material. LCMScalculated for C₂₇H₃₃FN₅O (M+H)⁺: m/z=462.3; Found: 462.3.

Example 25N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(dimethylamino)-5-fluoroquinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using dimethylamine hydrochloride, instead of(3R)-3-fluoropiperidine hydrochloride as starting material. LCMScalculated for C₂₄H₂₉FN₅O (M+H)⁺: m/z=422.2; Found: 422.3.

Example 26N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(2-fluoroethypamino]quinoline-8-carboxamide

Step 1. tert-Butyl((1S,3R,5S)-3-{3-[({5-fluoro-3-[(2-fluoroethyl)amino]quinolin-8-yl}carbonyl)amino]pyridin-4-yl}-5-methylcyclohexyl)carbamate

To a microwave vial was added tert-butyl[(1S,3R,5S)-3-(3-{[(3-bromo-5-fluoroquinolin-8-yl)carbonyl]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate(34.6 mg, 0.0621 mmol),dicyclohexyl-(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine-[2-(2-aminoethyl)phenyl](chloro)palladium(1:1) (7.4 mg, 0.0093 mmol), 2-fluoroethanamine hydrochloride and cesiumcarbonate (82.9 mg, 0.254 mmol). The vial was sealed with a teflonscrew-cap, evacuated and backfilled with nitrogen (this process wasrepeated a total of three times). To the reaction vial was addedanhydrous tert-butyl alcohol (0.44 mL). The resulting mixture was heatedat 90° C. for 5 h. After cooling to room temperature, the reactionmixture was diluted with water and DCM, the organic layer was separatedand concentrated. The crude was purified with flash chromatography(eluting with a gradient of 0-100% ethyl acetate in hexanes) to give thedesired product as a yellow foam. LCMS calculated for C₂₉H₃₆F₂N₅O₃(M+H)⁺: m/z=540.3; Found: 540.3.

Step 2.N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(2-fluoroethyl)amino]quinoline-8-carboxamide

The product from the previous step was treated with 1:1 DCM/TFA (2 mL)for 1 h. The volatiles were removed in vacuo and the residue wasdissolved in methanol and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) to give the desired product as ayellow solid (7.5 mg, 30% two steps). LCMS calculated for C₂₄H₂₈F₂N₅O(M+H)⁺: m/z=440.3; Found: 440.3.

Example 27N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-[(2,2-difluoroethypamino]-5-fluoroquinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 26, using 2,2-difluoroethanamine, instead of 2-fluoroethanaminehydrochloride as starting material. LCMS calculated for C₂₄H₂₇F₃N₅O(M+H)⁺: m/z=458.2; Found: 458.3.

Example 28N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(3,3-difluoropiperidin-1-yl)-5-fluoroquinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using 3,3-difluoropiperidine hydrochloride, instead of(3R)-3-fluoropiperidine hydrochloride as starting material. LCMScalculated for C₂₇H₃₁F₃N₅O (M+H)⁺: m/z=498.2; Found: 498.2.

Example 29N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(3S,4S)-3-fluoro-4-hydroxypiperidin-1-yl]quinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using (3S,4S)-3-fluoropiperidin-4-ol hydrochloride, insteadof (3R)-3-fluoropiperidine hydrochloride as starting material. LCMScalculated for C₂₇H₃₂F₂N₅O₂ (M+H)⁺: m/z=496.2; Found: 496.3.

Example 30N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-(4-methylpiperazin-1-yl)quinoline-8-carboxamide

This compound was prepared according to the procedure described inExample 2, using 1-methyl-piperazine, instead of (3R)-3-fluoropiperidinehydrochloride as starting material. LCMS calculated for C₂₇H₃₄FN₆O(M+H)⁺: m/z=477.3; Found: 477.3.

Example 31N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-(tetrahydro-2H-pyran-4-yl)quinoline-8-carboxamide

Step 1. Methyl3-(3,6-dihydro-2H-pyran-4-yl)-5-fluoroquinoline-8-carboxylate

To a microwave vial was added methyl3-bromo-5-fluoroquinoline-8-carboxylate (0.300 g, 1.06 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(0.288 g, 1.37 mmol), K₃PO₄ (0.448 g, 2.11 mmol) anddicyclohexyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (0.083 g, 0.10 mmol). The vial was sealed with a Teflon screw-cap,evacuated and backfilled with nitrogen (this process was repeated atotal of three times). To the vial was added 1,4-dioxane (4 mL) andwater (0.9 mL), and the mixture was heated at 75° C. for 6 h. Aftercooling to room temperature, the reaction mixture was filtered through apad of Celitewhich was further rinsed with EtOAc. The aqueous layer wasextracted with EtOAc (2×). The combined organic phases were washed withwater, brine and dried over Na₂SO₄, and then filtered. The filtrate wasconcentrated, and the residue was purified by flash chromatography(eluting with a gradient of 0-40% EtOAc in hexanes) to give the desiredproduct as white solid (0.29 g, 97%). LCMS calculated for C₁₆H₁₅FNO₃(M+H)⁺: m/z=288.1; Found: 288.1.

Step 2. Methyl5-fluoro-3-(tetrahydro-2H-pyran-4-yl)quinoline-8-carboxylate

A mixture of methyl3-(3,6-dihydro-2H-pyran-4-yl)-5-fluoroquinoline-8-carboxylate (290.0 mg,1.009 mmol) and 10% palladium on carbon (50 mg, 0.023 mmol) in ethylacetate (10 mL) was stirred under a balloon of H₂ for 3 h. The reactionmixture was filtered through a pad of Celite, and rinsed with EtOAc. Thefiltrate was concentrated to give the desired product as light green oil(0.265 g, 91%). LCMS calculated for C₁₆H₁₇FNO₃ (M+H)⁺: m/z=290.1; Found:290.1.

Step 3. 5-Fluoro-3-(tetrahydro-2H-pyran-4-yl)quinoline-8-carboxylic acid

A mixture of methyl5-fluoro-3-(tetrahydro-2H-pyran-4-yl)quinoline-8-carboxylate (265.0 mg,0.9160 mmol), lithium hydroxide (180 mg, 7.3 mmol), THF (4 mL), methanol(4 mL) and water (4 mL) was stirred at room temperature for 1 h. Thevolatiles were removed in vacuo, the residue was neutralized to pH 4-5with 1 N HCl solution. The resulting precipitate was filtered, rinsedwith water, and dried under vacuum to give the desired product as a tansolid (203 mg, 81%). LCMS calculated for C₁₅H₁₅FNO₃ (M+H)⁺: m/z=276.1;Found: 276.0.

Step 4. tert-Butyl{(1S,3R,5S)-3-[3-({[5-fluoro-3-(tetrahydro-2H-pyran-4-yl)quinolin-8-yl]carbonyl}amino)pyridin-4-yl]-5-methylcyclohexyl}carbamate

To a solution of of5-fluoro-3-(tetrahydro-2H-pyran-4-yl)quinoline-8-carboxylic acid (16.2mg, 0.0589 mmol) and tert-butyl[(1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl]carbamate (15.0mg, 0.0491 mmol) in DMF (1 mL) was addedN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (26.1 mg, 0.0688 mmol) and N,N-diisopropylethylamine(29 μL, 0.17 mmol). The reaction mixture was stirred at room temperatureovernight. The reaction mixture was diluted with water and DCM, and theaqueous layer was extracted with DCM once. The combined organic layerswere dried over Na₂SO₄, filtered and concentrated. The residue waspurified by prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.05% TFA, at flow rate of 60 mL/min) togive the desired product. LCMS calculated for C₃₂H₄₀FN₄O₄ (M+H)⁺:m/z=563.3; Found: 563.3.

Step 5.N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-(tetrahydro-2H-pyran-4-yl)quinoline-8-carboxamide

The product from the previous step was treated with 1:1 DCM/TFA (2 mL)for 1 h. The volatiles were removed in vacuo and the residue wasdissolved in methanol and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) to give the desired product as awhite solid (5.6 mg, 25% for two steps). LCMS calculated for C₂₇H₃₂FN₄O₂(M+H)⁺: m/z=463.2; Found: 463.2.

Example 32N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-3-methylmorpholino)quinoline-8-carboxamide

tert-Butyl (1S, 3R,5S)-3-(3-(5-fluoro-3-iodoquinoline-8-carboxamido)pyridin-4-yl)-5-methylcyclohexylcarbamate(20 mg, 0.03 mmol, Intermediate 1), cesium carbonate (29 mg, 0.09 mmol),RuPhos Pd G2 (5 mg, 0.006 mmol, Sigma-Aldrich) and a magnet bar wereplaced in a vial which was then evacuated and backfilled with nitrogenthree times. Then tert-butyl alcohol (2 mL) and (R)-3-methylmorpholine(6 μL, 0.06 mmol) were added. The reaction was stirred at 65° C.overnight. After this time the reaction was quenched by the addition ofwater and the product was extracted with ethyl acetate. Combined organicfractions were washed with brine, dried over sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure. Theresulting residue was treated with trifluoroacetic acid (1 mL) anddichloromethane (1 mL). After stirring at r.t. for 1 h, the reactionmixture was diluted with acetonitrile and neutralized with ammoniasolution. The mixture was purified by RP-HPLC (water XBridge C18 column,30 mm×100 mm, 5 μm particle size, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min) togive the desired product. LCMS calculated for C₂₇H₃₃FN₅O₂ (M+H)⁺m/z=478.3; found: 478.2. ¹H NMR (600 MHz, DMSO-d6) δ 13.03 (s, 1H), 9.17(s, 1H), 9.03 (d, J=3.0 Hz, 1H), 8.52 (d, J=5.4 Hz, 1H), 8.44 (dd,J=8.3, 6.2 Hz, 1H), 7.93 (br, 2H), 7.70 (d, J=3.0 Hz, 1H), 7.64-7.53 (m,2H), 4.34-4.25 (m, 1H), 4.04 (dd, J=11.5, 2.9 Hz, 1H), 3.82 (d, J=1.9Hz, 2H), 3.67 (td, J=11.6, 3.1 Hz, 1H), 3.56 (d, J=12.3 Hz, 1H),3.28-3.14 (m, 3H), 2.11 (d, J=12.1 Hz, 1H), 1.97 (d, J=12.4 Hz, 1H),1.92 (d, J=13.1 Hz, 1H), 1.79-1.66 (m, 1H), 1.52 (q, J=12.1 Hz, 1H),1.19 (d, J=12.4 Hz, 1H), 1.16 (d, J=6.7 Hz, 3H), 1.08 (q, J=12.1 Hz,1H), 1.01 (d, J=6.6 Hz, 3H) ppm.

Example 33N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-3-methylmorpholino)quinoline-8-carboxamide

This compound was synthesized as described in Example 32, using(S)-3-methylmorpholine. LCMS calculated for C₂₇H₃₃FN₅O₂ (M+H)⁺m/z=478.3; found: 478.3. ¹H NMR (600 MHz, DMSO-d6) δ 13.02 (s, 1H), 9.19(s, 1H), 9.07 (d, J=3.0 Hz, 1H), 8.50 (d, J=5.3 Hz, 1H), 8.44 (dd,J=8.3, 6.2 Hz, 1H), 7.93 (br, 2H), 7.70 (d, J=3.0 Hz, 1H), 7.59 (dd,J=9.5, 8.4 Hz, 1H), 7.53 (d, J=5.3 Hz, 1H), 4.34-4.27 (m, 1H), 4.05 (dd,J=1.14, 3.2 Hz, 1H), 3.82 (s, 2H), 3.67 (td, J=11.6, 3.1 Hz, 1H), 3.55(d, J=12.2 Hz, 1H), 3.23 (tt, J=1-4.5, 8.0 Hz, 3H), 2.13 (d, J=11.8 Hz,1H), 1.98 (d, J=11.8 Hz, 1H), 1.91 (d, J=12.7 Hz, 1H), 1.72 (br, 1H),1.62-1.47 (m, 1H), 1.20-1.16 (m, 1H), 1.15 (d, J=6.7 Hz, 3H), 1.08 (q,J=12.1 Hz, 1H), 0.97 (d, J=6.6 Hz, 3H) ppm.

Example 34N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using (R)-2-methylpyrrolidine. LCMS calculated for C₂₇F₃₃FN₅O (M+H)⁺m/z=462.3; found: 462.2.

Example 35N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2,5-dimethylmorpholino)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using 2,5-dimethylmorpholine. LCMS calculated for C₂₈H₃₅FN₅O₂ (M+H)⁺m/z=492.3; found: 492.2.

Example 36N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2,5-dimethylpyrrolidin-1-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using 2,5-dimethylpyrrolidine. LCMS calculated for C₂₈H₃₅FN₅O (M+H)⁺m/z=476.3; found: 476.3.

Example 37N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2,6-dimethylmorpholino)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using 2,6-dimethylmorpholine. LCMS calculated for C₂₈H₃₅FN₅O₂ (M+H)⁺m/z=492.3; found: 492.3.

Example 38N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-2-methylmorpholino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using (S)-2-methylmorpholine. LCMS calculated for C₂₇H₃₃FN₅O₂ (M+H)⁺m/z=478.3; found: 478.3.

Example 39N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using (S)-2-methylpyrrolidine. LCMS calculated for C₂₇H₃₃FN₅O (M+H)⁺m/z=462.3; found: 462.2.

Example 40N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(4,4-difluoropiperidin-1-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using 4,4-difluoropiperidine. LCMS calculated for C₂₇H₃₁F₃N₅O (M+H)⁺m/z=498.2; found: 498.2.

Example 41N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-hydroxy-4-methylpiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using 4-methylpiperidin-4-ol. LCMS calculated for C₂₈H₃₅FN₅O₂ (M+H)⁺m/z=492.3; found: 492.3.

Example 42N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((2,2-difluoroethyl)(methyl)amino)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using 2,2-difluoro-N-methylethanamine. LCMS calculated for C₂₅H₂₉F₃N₅O(M+H)⁺ m/z=472.2; found: 472.2.

Example 43N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(2-methylpiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using 2-methylpiperidine. LCMS calculated for C₂₈H₃₅FN₅O (M+H)⁺m/z=476.3; found: 476.3. ¹H NMR (600 MHz, DMSO-d6) δ 13.10 (s, 1H), 9.18(s, 1H), 9.03 (d, J=3.0 Hz, 1H), 8.52 (d, J=5.4 Hz, 1H), 8.41 (dd,J=8.3, 6.2 Hz, 1H), 7.92 (br, 2H), 7.66 (d, J=3.0 Hz, 1H), 7.60-7.52 (m,2H), 4.53-4.43 (m, 1H), 3.73-3.64 (m, 1H), 3.26-3.16 (m, 1H), 3.08 (td,J=12.2, 3.0 Hz, 1H), 2.10 (d, J=11.8 Hz, 1H), 1.95 (dd, J=22.9, 12.7 Hz,2H), 1.91-1.82 (m, 2H), 1.77-1.65 (m, 3H), 1.66-1.58 (m, 2H), 1.54 (q,J=12.0 Hz, 1H), 1.18 (q, J=12.2 Hz, 1H), 1.13 (d, J=6.7 Hz, 3H),1.11-1.05 (m, 1H), 1.01 (d, J=6.6 Hz, 3H) ppm.

Example 44N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-hydroxypiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using piperidin-4-ol. LCMS calculated for C₂₇H₃₃FN₅O₂ (M+H)⁺ m/z=478.3;found: 478.3.

Example 45N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(4-cyanopiperidin-1-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using piperidine-4-carbonitrile. LCMS calculated for C₂₈H₃₂FN₆O (M+H)⁺m/z=487.3; found: 487.2.

Example 46N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-methylpiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using 4-methylpiperidine. LCMS calculated for C₂₈H₃₅FN₅O (M+H)⁺m/z=476.3; found: 476.3.

Example 47N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-0R)-2-(methoxymethyl)pyrrolidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using (R)-2-(methoxymethyl)pyrrolidine. LCMS calculated for C₂₈H₃₅FN₅O₂(M+H)⁺ m/z=492.3; found: 492.3.

Example 48N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-0S)-2-(methoxymethyl)pyrrolidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using (S)-2-(methoxymethyl)pyrrolidine. LCMS calculated for C₂₈H₃₅FN₅O₂(M+H)⁺ m/z=492.3; found: 492.2.

Example 49N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-3-methoxypyrrolidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using (R)-3-methoxypyrrolidine. LCMS calculated for C₂₇H₃₃FN₅O₂ (M+H)⁺m/z=478.3; found: 478.2.

Example 50N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-3-methoxypyrrolidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using (S)-3-methoxypyrrolidine. LCMS calculated for C₂₇H₃₃FN₅O₂ (M+H)⁺m/z=478.3; found: 478.2.

Example 51N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2-methoxyethyl)(methyl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using 2-methoxy-N-methylethanamine. LCMS calculated for C₂₆H₃₃FN₅O₂(M+H)⁺ m/z=466.3; found: 466.2.

Example 52N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((S)-1-cyclopropylethylamino)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using (S)-1-cyclopropylethanamine. LCMS calculated for C₂₇H₃₃FN₅O (M+H)⁺m/z=462.3; found: 462.2.

Example 53N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-3-methylbutan-2-ylamino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using (S)-3-methylbutan-2-amine. LCMS calculated for C₂₇H₃₅FN₅O (M+H)⁺m/z=464.3; found: 464.3.

Example 54N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-3-methylbutan-2-ylamino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using (R)-3-methylbutan-2-amine. LCMS calculated for C₂₇H₃₅FN₅O (M+H)⁺m/z=464.3; found: 464.3.

Example 55N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl(propyl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using N-methylpropan-1-amine. LCMS calculated for C₂₆H₃₃FN₅O (M+H)⁺m/z=450.3; found: 450.3.

Example 56N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(isopropyhmethyl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using N-methylpropan-2-amine. LCMS calculated for C₂₆H₃₃FN₅O (M+H)⁺m/z=450.3; found: 450.3.

Example 57N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2-ethylpiperidin-1-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using 2-ethylpiperidine. LCMS calculated for C₂₉H₃₇FN₅O (M+H)⁺m/z=490.3; found: 490.3.

Example 58N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2-(difluoromethyl)piperidin-1-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using 2-(difluoromethyl)piperidine. LCMS calculated for C₂₈H₃₃F₃N₅O(M+H)⁺ m/z=512.3; found: 512.2.

Example 59N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5,6′-difluoro-3,8′-biquinoline-8-carboxamide

ter t-Butyl(1S,3R,5S)-3-(3-(5-fluoro-3-iodoquinoline-8-carboxamido)pyridin-4-yl)-5-methylcyclohexylcarbamate(20 mg, 0.03 mmol, Intermediate 1), 6-fluoroquinolin-8-ylboronic acid(9.4 mg, 0.049 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), potassium phosphate (20 mg, 0.096mmol) and a magnet bar were placed in a vial with septum which was thenevacuated and backfilled with nitrogen three times. 1,4-Dioxane (2.5 mL)and degassed water (0.3 mL) were added and the reaction mixture wasstirred at 65° C. for 1 h. Then the reaction was diluted with ethylacetate. The resulting solution was washed with brine, dried over sodiumsulfate and solvent evaporated. Trifluoroacetic acid (1 mL) anddichloromethane (1 mL) were added to the obtained crude product and thereaction mixture was stirred at r.t. for 1 h. After dilution withacetonitrile and neutralization by the addition of the ammonia solutionthe desired product was purified by RP-HPLC (water XBridge C18 column,30 mm×100 mm, 5 μm particle size, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).LCMS calculated for C₃₁H₂₈F₂N₅O (M+H)⁺ m/z=524.2; found: 524.1.

Example 60N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5,5′-difluoro-3,8′-biquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 59,using 5-fluoroquinolin-8-ylboronic acid. LCMS calculated for C₃₁H₂₈F₂N₅O(M+H)⁺ m/z=524.2; found: 524.1.

Example 61N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(6-(trifluoromethyl)pyridin-3-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 59,using 6-(trifluoromethyl)pyridin-3-ylboronic acid. LCMS calculated forC₂₈H₂₆F₄N₅O (M+H)⁺ m/z=524.2; found: 524.1.

Example 62N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(1-ethyl-1H-pyrazol-4-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 59,using1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.LCMS calculated for C₂₇H₃₀FN₆O (M+H)⁺ m/z=473.2; found: 473.2.

Example 63N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(1,3-dimethyl-1H-pyrazol-4-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 59,using1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.LCMS calculated for C₂₇H₃₀FN₆O (M+H)⁺ m/z=473.2; found: 473.2.

Example 64N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(1-methyl-1H-pyrazol-4-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 59,using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.LCMS calculated for C₂₆H₂₈FN₆O (M+H)⁺ m/z=459.2; found: 459.2.

Example 65N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(3-methyl-1H-pyrazol-4-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 59,using tert-butyl5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.LCMS calculated for C₂₆H₂₈FN₆O (M+H)⁺ m/z=459.2; found: 459.2.

Example 66N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(1H-pyrazol-4-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 59,using tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate.LCMS calculated for C₂₅H₂₆FN₆O (M+H)⁺ m/z=445.2; found: 445.2.

Example 67 N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((R)-3-methylmorpholino)quinoline-8-carboxamide

tert-Butyl(1S,3R,5S)-3-(3-(3-bromoquinoline-8-carboxamido)pyridin-4-yl)-5-methylcyclohexylcarbamate(16 mg, 0.03 mmol, Intermediate 2), cesium carbonate (29 mg, 0.09 mmol),RuPhos Pd G2 (5 mg, 0.006 mmol, Sigma-Aldrich) and a magnet bar wereplaced in a vial which was then evacuated and backfilled with nitrogenthree times. Then tert-butyl alcohol (2 mL) and (R)-3-methylmorpholine(6 μL, 0.06 mmol) were added. The reaction mixture was stirred at 65° C.overnight. After this time the reaction was quenched by the addition ofwater and the product was extracted with ethyl acetate. Combined organicfractions were washed with brine, dried over sodium sulfate and thesolvents were evaporated under reduced pressure. Trifluoroacetic acid (1mL) and dichloromethane (1 mL) were added to the obtained crude productand the reaction mixture was stirred at r.t. for 1 h. After dilutionwith acetonitrile and neutralization by the addition of ammoniasolution, the desired product was purified by RP-HPLC (water XBridge C18column, 30 mm×100 mm, 5 μm particle size, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).LCMS calculated for C₂₇H₃₄N₅O₂ (M+H)⁺ m/z=460.3; found: 460.2.

Example 68N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((R)-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 67,using (R)-2-methylpyrrolidine. LCMS calculated for C₂₇H₃₄N₅O (M+H)⁺m/z=444.3; found: 444.2.

Example 69N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((S)-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 67,using (S)-2-methylpyrrolidine. LCMS calculated for C₂₇H₃₄N₅O (M+H)⁺m/z=444.3; found: 444.3.

Example 70N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2-methylpiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 67,using 2-methylpiperidine. LCMS calculated for C₂₈H₃₆N₅O (M+H)⁺m/z=458.3; found: 458.2.

Example 71N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2-(difluoromethyl)piperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 67,using 2-(difluoromethyl)piperidine. LCMS calculated for C₂₈H₃₄F₂N₅O(M+H)⁺ m/z=494.3; found: 494.3.

Example 72N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((2,2-difluoroethyl)(methyl)aminolouinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 67,using 2,2-difluoro-N-methylethanamine. LCMS calculated for C₂₅H₃₀F₂N₅O(M+H)⁺ m/z=454.2; found: 454.2.

Example 73N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-thiomorpholinoquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using thiomorpholine. LCMS calculated for C₂₆H₃₁FN₅OS (M+H)⁺ m/z=480.2;found: 480.2.

Example 74N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(4-(N,N-dimethylsulfamoyl)piperazin-1-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using N,N-dimethylpiperazine-1-sulfonamide. LCMS calculated forC₂₈H₃₇FN₇O₃S (M+H)⁺ m/z=570.3; found: 570.2.

Example 75N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-methyl-3-oxopiperazin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using 1-methylpiperazin-2-one. LCMS calculated for C₂₇H₃₂FN₆O₂ (M+H)⁺m/z=491.3; found: 491.2.

Example 76N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(azepan-1-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using azepane. LCMS calculated for C₂₈H₃₅FN₅O (M+H)⁺ m/z=476.3; found:476.2.

Example 77N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using 3-oxa-8-azabicyclo[3.2.1]octane. LCMS calculated for C₂₈H₃₃FN₅O₂(M+H)⁺ m/z=490.3; found: 490.2.

Example 78N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(2-oxopyrrolidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using pyrrolidin-2-one. LCMS calculated for C₂₆H₂₉FN₅O₂ (M+H)⁺m/z=462.2; found: 462.2.

Example 79N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(indolin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using indoline. LCMS calculated for C₃₀H₃₁FN₅O (M+H)⁺ m/z=496.2; found:496.2.

Example 80N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane. LCMS calculated forC₂₇H₃₁FN₅O₂ (M+H)⁺ m/z=476.2; found: 476.2.

Example 81N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using 6-oxa-3-azabicyclo[3.1.1]heptane. LCMS calculated for C₂₇H₃₁FN₅O₂(M+H)⁺ m/z=476.2; found: 476.2.

Example 82N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(4-(dimethylcarbamoyl)piperazin-1-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using N,N-dimethylpiperazine-1-carboxamide. LCMS calculated forC₂₉H₃₇FN₇O₂ (M+H)⁺ m/z=534.3; found: 534.2.

Example 83N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl(phenyl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using N-methylaniline. LCMS calculated for C₂₉H₃₁FN₅O (M+H)⁺ m/z=484.2;found: 484.2.

Example 84N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using hexahydropyrrolo[1,2-a]pyrazin-6(7H)-one. LCMS calculated forC₂₉H₃₄FN₆O₂ (M+H)⁺ m/z=517.3; found: 517.3.

Intermediate 3. (S)-3-Methyl-1-(methylsulfonyl)piperazine (HCl salt)

Methanesulfonyl chloride (232 μL, 3.00 mmol) was slowly added at 0° C.to a solution of tert-butyl (2S)-2-methylpiperazine-1-carboxylate (300mg, 1.5 mmol) and triethylamine (835 μL, 6 mmol) in methylene chloride(6 mL). After stirring at r.t. for 1 h, reaction mixture was carefullyquenched by addition of water and the desired product was extracted withethyl acetate. The organic phase was washed with brine, dried oversodium sulfate, and filtered. The filtrate was concentrated underreduced pressure. The resulting residue was purified by Biotage Isolera™(flash purification system with hexane/ethyl acetate at a ratio from 0to 100%) to give tert-butyl(2S)-2-methyl-4-(methylsulfonyl)piperazine-1-carboxylate (404 mg, 97%).LCMS calculated for C₆H₁₅N₂O₂S (M+H-Boc)⁺ m/z=179.1; found: 179.1.

A 4.0 M solution of hydrogen chloride in dioxane (4 mL, 16 mmol) wasadded to the tert-butyl(2S)-2-methyl-4-(methylsulfonyl)piperazine-1-carboxylate (404 mg, 1.45mmol). After stirring at r.t. for 1 h, solvent was evaporated underreduced pressure and the resulting product was dried under vacuum for 1h. LCMS calculated for C₆H₁₅N₂O₂S (M+H)⁺ m/z=179.1; found: 179.1.

Example 85N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-34(S)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using Intermediate 3. LCMS calculated for C₂₈H₃₆FN₆O₃S (M+H)⁺ m/z=555.3;found: 555.2.

Intermediate 4. (R)-3-Methyl-1-(methylsulfonyl)piperazine (HCl salt)

This compound was synthesized by the same way as Intermediate 3, usingtert-butyl (2R)-2-methylpiperazine-1-carboxylate. LCMS calculated forC₆H₁₅N₂O₂S (M+H)⁺ m/z=179.1; found: 179.1.

Example 86N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-2-methyl-4-(methylsulfonyl)piperazin-1-ypouinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using Intermediate 4. LCMS calculated for C₂₈H₃₆FN₆O₃S (M+H)⁺ m/z=555.3;found: 555.2.

Intermediate 5.(1R,4R)-2-(Methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptane (HCl salt)

This compound was synthesized according to the procedures ofIntermediate 3, using (1R, 4R)-tert-butyl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. LCMS calculated forC₆H₁₃N₂O₂S (M+H)⁺ m/z=177.1; found: 177.1.

Example 87N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((1R,4R)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 32,using Intermediate 5. LCMS calculated for C₂₈H₃₄FN₆O₃S (M+H)⁺ m/z=553.2;found: 553.2.

Intermediate 6. (S)-Methyl 3-methylpiperazine-1-carboxylate (HCl salt)

Methyl chloroformate (230 μL, 3 mmol) was slowly added at 0° C. to asolution of tert-butyl (2S)-2-methylpiperazine-1-carboxylate (300 mg,1.5 mmol) and triethylamine (835 μL, 6 mmol) in methylene chloride (6mL). After stirring at r.t. for 1 h, reaction mixture was carefullyquenched by addition of water and the desired product was extracted withethyl acetate. The organic phase was washed with brine, dried oversodium sulfate and solvent was evaporated under reduced pressure. Crudematerial was purified by Biotage Isolera™ to give (S)-1-tert-butyl4-methyl 2-methylpiperazine-1,4-dicarboxylate (378 mg, 97%). LCMScalculated for C₇H₁₅N₂O₂ (M+H-Boc)⁺ m/z=159.1; found: 159.1.

A 4.0 M solution of hydrogen chloride in dioxane (4 mL, 16 mmol) wasadded to the (S)-1-tert-butyl 4-methyl2-methylpiperazine-1,4-dicarboxylate (378 mg, 1.45 mmol). After stirringat r.t. for 1 h, solvent was evaporated under reduced pressure and theproduct was dried under vacuum for 1 h. LCMS calculated for C₇H₁₅N₂O₂(M+H)⁺ m/z=159.1; found: 159.1.

Example 88 (S)-Methyl 4-(8-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-ylcarbamoyl)-5-fluoroquinolin-3-yl)-3-methylpiperazine-1-carboxylate

This compound was synthesized according to the procedures of Example 32,using Intermediate 6. LCMS calculated for C₂₉H₃₆FN₆O₃ (M+H)⁺ m/z=535.3;found: 535.2.

Intermediate 7. (R)-Methyl 3-methylpiperazine-1-carboxylate (HCl salt)

This compound was synthesized according to the procedures ofIntermediate 6, using tert-butyl (2R)-2-methylpiperazine-1-carboxylate.LCMS calculated for C₇H₁₅N₂O₂ (M+H)⁺ m/z=159.1; found: 159.1.

Example 89 (R)-Methyl4-(8-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-ylcarbamoyl)-5-fluoroquinolin-3-yl)-3-methylpiperazine-1-carboxylate

This compound was synthesized according to the procedures of Example 32,using Intermediate 7. LCMS calculated for C₂₉H₃₆FN₆O₃ (M+H)⁺ m/z=535.3;found: 535.2.

Intermediate 8. (1R,4R)-Methyl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (HCl salt)

This compound was synthesized according to the procedures ofIntermediate 6, using (1R, 4R)-tert-butyl2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. LCMS calculated forC₇H₁₃N₂O₂ (M+H)⁺ m/z=157.1; found: 157.1.

Example 90 (1R,4R)-Methyl 5-(8-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-ylcarbamoyl)-5-fluoroquinolin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

This compound was synthesized according to the procedures of Example 32,using Intermediate 8. LCMS calculated for C₂₉H₃₄FN₆O₃ (M+H)⁺ m/z=533.3;found: 533.2.

Example 91N-{4-[(1R,3S,5S)-3-amino-5-methylcyclohexyl]pyridin-3-yl}-3-(2,6-difluorophenyl)-5-fluorocinnoline-8-carboxamide

Step 1. 1-(2-Bromo-3-fluorophenyl)-3,3-diethyltriaz-1-ene

A solution of 2-bromo-3-fluoroaniline (24.2 g, 127 mmol) in THF (122mL), acetonitrile (122 mL) and water (1-41 mL) was cooled to −5° C. witha salt/ice bath. Then 12.0 M aqueous hydrogen chloride (84.9 mL, 1020mmol) was added followed by dropwise addition of a solution of sodiumnitrite (17.6 g, 255 mmol) in water (95 mL) and acetonitrile (32 mL).The reaction mixture was stirred at −5° C. for 30 min. The yellowsuspension was then transferred slowly via cannula to a stirred solutionof N-ethylethanamine (263.5 mL, 2547 mmol) in water (765 mL) andacetonitrile (765 mL) cooled to 0° C. The mixture was stirred at 0° C.for 30 min. The mixture was diluted with 300 mL satd. NaHCO₃ andextracted with EtOAc (500 ml). The organic layer was separated, washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude product was purified with flash chromatography (eluting with agradient of 0-15% DCM in hexanes) to the obtain the desired product as ared oil (33.9 g, 97%). LCMS calculated for C₁₀H₁₄BrFN₃ (M+H)⁺:m/z=274.0, 276.0; Found: 274.0, 276.0.

Step 2.3,3-Diethyl-1-{3-fluoro-2-[(trimethylsilyl)ethynyl]phenyl}triaz-1-ene

To a round bottom flask was addedtetrakis(triphenylphosphine)palladium(0) (7.1 g, 6.2 mmol). The flaskwas sealed and evacuated under vacuum and refilled by N₂. (this processwas repeated three times). Pyrrolidine (270 mL, 3200 mmol) was addedfollowed by 1-(2-bromo-3-fluorophenyl)-3,3-diethyltriaz-1-ene (33.9 g,124 mmol). The (trimethylsilyl)acetylene (28.0 mL, 198 mmol) was addedusing a syringe pump over 48 h at 95° C. After cooling to roomtemperature, the solvent was evaporated in vacuo. The residue wasdissolved in EtOAc and diluted with water. The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified with flash chromatography (eluting with a gradientof 0-15% DCM in hexanes) to give the desired product as a red oil (28.0g, 78%). LCMS calculated for C₁₅H₂₃FN₃Si (M+H)⁺: m/z=292.2; Found:292.2.

Step 3. 3,3-Diethyl-1-(2-ethynyl-3-fluorophenyl)triaz-1-ene

To a solution of3,3-diethyl-1-{3-fluoro-2-[(trimethylsilyl)ethynyl]phenyl}triaz-1-ene(23.6 g, 81.0 mmol) in THF (650 mL) was added 1.0 Mtetra-n-butylammonium fluoride in THF (85.0 mL, 85.0 mmol). Theresulting mixture was stirred at room temperature for 1 h. The reactionmixture was diluted with ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate once. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified with flash chromatography (eluting with agradient of 0-10% ethyl acetate in hexanes) to give the desired productas a red oil (15.2 g, 86%). LCMS calculated for C₁₂H₁₅FN₃ (M+H)⁺:m/z=220.1; Found: 220.1.

Step 4. 5-Fluorocinnoline

A solution of 3,3-diethyl-1-(2-ethynyl-3-fluorophenyl)triaz-1-ene (1.4g, 6.2 mmol) in 1,2-dichlorobenzene (1-4 mL, 120 mmol) was placed in amicrowave vial and was sealed. The mixture was heated in the microwavefor 55 min at 220° C. The crude product was dissolved in DCM and waspurified on a 50 g column (eluting with a gradient of 0-50% ethylacetate in hexanes) to give the desired product as a solid (0.52 g,56%). LCMS calculated for C₈H₆FN₂ (M+H)⁺: m/z=1-49.0; Found: 1-49.1.

Step 5. 5-Fluoro-8-iodocinnoline and 5-Fluoro-3,8-diiodocinnoline

To a flask was added 5-fluorocinnoline (4.9 g, 33 mmol), tetrahydrofuran(130 mL) and a 1.9 M zinc dichloride in 2-methyltetrahydrofuran solution(17.4 mL, 33.1 mmol) at room temperature, followed by the immediateaddition of 1.0 M lithiumchloride-chloro(2,2,6,6-tetramethylpiperidin-1-yl)magnesium (1:1) in THF(66.2 mL, 66.2 mmol). The reaction mixture was then heated at 50° C. for3 h. The reaction mixture was then cooled to 0° C. and cannulated into asolution of iodine (16.8 g, 66.2 mmol) in THF (65 mL) pre-cooled to 0°C. The reaction mixture was stirred at 0° C. for 30 min, then at roomtemperature for 1 h. The reaction was quenched with a saturated aqueoussolution of Na₂S₂O₃ (200 mL) and extracted with ethyl acetate (3×) anddried over Na₂SO₄, filtered and concentrated. The crude product waspurified by flash chromatography (eluting with a gradient of 0-30% ethylacetate in hexanes) to give 5-fluoro-8-iodocinnoline as yellow solid(3.8 g, 42%). ¹H NMR (400 MHz, CDCl₃) δ 9.51 (d, J=5.9 Hz, 1H), 8.41(dd, J=8.1, 5.5 Hz, 1H), 8.03 (d, J=5.9 Hz, 1H), 7.25 (m, 1H), LCMScalculated for C₈H₅FIN₂ (M+H)⁺: m/z=274.9; Found: 275.0.5-Fluoro-3,8-diiodocinnoline was isolated as a brown solid (1.5 g, 12%).LCMS calculated for C₈H₄FI₂N₂ (M+H)⁺: m/z=400.8; Found: 400.8.

Step 6. 5-Fluoro-8-vinylcinnoline

A flask charged with 5-fluoro-8-iodocinnoline (3.80 g, 13.9 mmol),4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (3.53 mL, 20.8 mmol),dicyclohexyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (710 mg, 0.90 mmol) and tripotassium phosphate hydrate (7.03 g,30.5 mmol) was evacuated and refilled with nitrogen (this process wasrepeated three times). 1,4-Dioxane (76 mL) and water (25 mL) were addedto flask. The resulting mixture was stirred at 70° C. for 1 h. Aftercooling to room temperature, the reaction mixture was diluted with waterand ethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified with flashchromatography (eluting with a gradient of 0-30% ethyl acetate inhexanes) to give the desired product as a yellow solid (1.9 g, 78%).LCMS calculated for C₁₀H₈FN₂ (M+H)⁺: m/z=175.1; Found: 175.1.

Step 7. 5-Fluoro-3-iodo-8-vinylcinnoline

To a solution of 5-fluoro-8-vinylcinnoline (358 mg, 2.06 mmol) in THF(5.4 mL) was added boron trifluoride etherate (286 μL, 2.26 mmol) at 0°C. dropwise. After stirring for 15 min, the solution was cooled to −78°C. and 0.5 M bis(2,2,6,6-tetramethylpiperidinyl)magnesium, lithiumchloride (TMP₂Mg 2LiCl) in THF (4.52 mL, 2.26 mmol) was added dropwise.The reaction mixture was stirred for 10 min at −78° C., then wascannulated into a solution of iodine (1.04 g, 4.11 mmol) in THF (3.2 mL)at −78° C. The reaction mixture was allowed to warm to room temperatureand stirred overnight. Then the reaction mixture was quenched with aq.Na₂S₂O₃ solution, extracted with ethyl acetate (2×) and dried overNa₂SO₄, filtered and concentrated. The crude was purified with flashchromatography (eluting with a gradient of 0-80% ethyl acetate inhexanes) to give the desired product as a yellow solid (0.26 g, 41%). ¹HNMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 8.10 (m, 1H), 7.97 (m, 1H), 7.44(t, J=8.5 Hz, 1H) 6.09 (d, J=17.7 Hz, 1H), 5.65 (d, J=11.1 Hz, 1H). LCMScalculated for C₁₀H₇FIN₂ (M+H)⁺: m/z=301.0; Found: 301.0.

Step. 8. 5-Fluoro-3-iodocinnoline-8-carbaldehyde

To a solution of 5-fluoro-3-iodo-8-vinylcinnoline (255 mg, 0.850 mmol)in THF (10 mL) and water (0.8 mL) was added 0.16 M osmium tetraoxide inwater (110 μL, 0.017 mmol) and sodium metaperiodate (0.73 g, 3.4 mmol).The resulting mixture was stirred at 60° C. for 1 h. The mixture wasfiltered through a pad of Celite, and rinsed with THF. The organic layerwas concentrated in vacuo. The residue was purified with flashchromatography (eluting with a gradient of 0-30% ethyl acetate inhexanes) to give the desired compound as a yellow powder (1-43 mg, 56%).¹H NMR (400 MHz, CDCl₃) δ 11.56 (s, 1H), 8.63 (s, 1H), 8.48 (dd, J=8.1,5.8 Hz, 1H), 7.60 (t, J=8.3 Hz, 1H). LCMS calculated for C₉H₅FIN₂O(M+H)⁺: m/z=302.9; Found: 302.9.

Step 9. 5-Fluoro-3-iodocinnoline-8-carboxylic acid

A solution of 5-fluoro-3-iodocinnoline-8-carbaldehyde (142 mg, 0.470mmol) and sodium dihydrogenphosphate (20.6 mg, 0.172 mmol) inacetonitrile (2.5 mL) and water (0.50 mL) was cooled in an ice bath.Hydrogen peroxide (59 μL, 1.9 mmol) was added followed by solid sodiumchlorite (110 mg, 0.96 mmol), and the mixture was stirred for 3 h. Thesolvent was removed in vacuo. The residue was partitioned between ethylacetate and water. Then 1 M HCl solution was added to adjust pH to 1.The aqueous layer was extracted with DCM (3×), and the combined organicphases were dried over MgSO₄, filtered, and concentrated to give productas a red solid (110 mg, 74%). LCMS calculated for C₉H₅FIN₂O₂ (M+H)⁺:m/z=318.9; Found: 318.9.

Step 10. tert-Butyl[(1S,3R,5S)-3-(3-{[(5-fluoro-3-iodocinnolin-8-yl)carbonyl]amino}pyridin-4-yl-5-methylcyclohexyl]carbamate

A solution of 5-fluoro-3-iodocinnoline-8-carboxylic acid (120 mg, 0.377mmol) and tert-butyl[(1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexyl]carbamate (96.0mg, 0.34 mmol) in DMF (1.0 mL) was added toN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (174 mg, 0.458 mmol) and N,N-diisopropylethylamine(160 μL, 0.94 mmol). The resulting mixture was stirred at roomtemperature overnight. The reaction was quenched with water, and theaqueous layer was extracted with DCM once. The combined organic layerswere dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography (eluting with a gradient of 0-100%ethyl acetate/hexanes) to give the desired product as yellow solid (160mg, 84%). LCMS calculated for C₂₆H₃₀FIN₅O₃ (M+H)⁺: m/z=606.1; Found:606.1.

Step 11. tert-Butyl{(1S,3R,5S)-3-[3-({[3-(2,6-difluorophenyl)-5-fluorocinnolin-8-yl]carbonyl}amino)pyridin-4-yl]-5-methylcyclohexyl}carbamate

A microwave vial was charged with tert-butyl[(1S,3R,5S)-3-(3-{[(5-fluoro-3-iodocinnolin-8-yl)carbonyl]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate(20.2 mg, 0.0334 mmol),2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.8 mg,0.0534 mmol),dicyclohexyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2.3 mg, 0.0029 mmol) and tripotassium phosphate hydrate (16.9 mg,0.0735 mmol). The vial was sealed and evacuated under vacuum andrefilled with nitrogen (this process was repeated three times),1,4-dioxane (0.36 mL) and water (0.12 mL) was added. The resultingmixture was stirred at 70° C. for 1 h. After cooling to roomtemperature, the reaction mixture was diluted with water and DCM. Theorganic layer was concentrated and purified with flash chromatography(eluting with a gradient of 0-100% ethyl acetate in hexanes) to give thedesired product as a yellow oil (10.2 mg, 52%). LCMS calculated forC₃₂H₃₃F₃N₅O₃ (M+H)⁺: m/z=592.3; Found: 592.3.

Step 12.N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(2,6-dilluorophenyl)-5-fluorocinnoline-8-carboxamide

The compound from the previous step was treated with 1:1 DCM/TFA (2 mL)for 1 h. The volatiles were removed in vacuo and the residue wasdissolved in methanol and purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) to give the desired product as ayellow solid (6.2 mg, 73%). LCMS calculated for C₂₇H₂₅F₃N₅O (M+H)⁺:m/z=492.2; Found: 492.2.

Example 92N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-ethyl-5-fluorocinnoline-8-carboxamide

Step 1. tert-Butyl[(1S,3R,5S)-3-(3-{[(5-fluoro-3-vinykinnolin-8-yl)carbony]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate

A microwave vial charged with tert-butyl[(1S,3R,5S)-3-(3-{[(5-fluoro-3-iodocinnolin-8-yl)carbonyl]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate(25.1 mg, 0.0414 mmol),dicyclohexyl-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2.9 mg, 0.0036 mmol) and tripotassium phosphate hydrate (21.0 mg,0.0913 mmol) was sealed, evacuated, and refilled with nitrogen (thisprocess was repeated three times). To the vial was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (11.2 μL, 0.0663 mmol),1,4-dioxane (0.45 mL) and water (0.15 mL). The resulting mixture wasstirred at 70° C. for 1 h. After cooling to room temperature, thereaction mixture was diluted with water and DCM. The organic layer wasconcentrated and purified with flash chromatography (eluting with agradient of 0-100% ethyl acetate in hexanes) to give the desired productas a yellow oil (13.2 mg, 63%). LCMS calculated for C₂₈H₃₃FN₅O₃ (M+H)⁺:m/z=506.3; Found: 506.2.

Step 2.N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-ethyl-5-fluorocinnoline-8-carboxamide

To a solution of tert-butyl[(1S,3R,5S)-3-(3-{[(5-fluoro-3-vinylcinnolin-8-yl)carbonyl]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate(13.2 mg) in methanol (2 mL) was added 10% palladium on carbon (5 mg).The resulting suspension was stirred under a H₂ balloon for 2 h. Afterfiltration and concentration, the residue was treated with 1:1 DCM/TFA(2 mL) for 1 h. The volatiles were removed in vacuo and the residue wasdissolved in methanol and purified by prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) to give the desired product asyellow solid (4.2 mg, 40%). LCMS calculated for C₂₃H₂₇FN₅O (M+H)⁺:m/z=408.2; Found: 408.1.

Example 93.N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-(2-methylpiperidin-1-yl)cinnoline-8-carboxamide

Step 1. tert-Butyl{(1S,3R,5S)-3-[3-({[5-fluoro-3-(2-methylpiperidin-1-yl)cinnolin-8-yl]carbonyl}amino)pyridin-4-yl]-5-methylcyclohexyl}carbamate

To a vial was charged with tert-butyl[(1S,3R,5S)-3-(3-{[(5-fluoro-3-iodocinnolin-8-yl)carbonyl]amino}pyridin-4-yl)-5-methylcyclohexyl]carbamate(21.0 mg, 0.0347 mmol),dicyclohexyl-(2′,6′-diisopropoxybiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium(1:1) (2.7 mg, 0.0035 mmol) and cesium carbonate (46.3 mg, 0.142 mmol).The vial was sealed with a teflon screw-cap, evacuated and backfilledwith nitrogen (this process was repeated a total of three times). Asolution of 2-methylpiperidine (20.4 μL, 0.173 mmol) in anhydrousdioxane (0.4 mL) was added. The mixture was heated at 80° C. overnight.After cooling to room temperature, the reaction mixture was diluted withwater and DCM, and the organic layer was separated and concentrated. Thecrude product was purified with flash chromatography (eluting with agradient of 0-100% ethyl acetate in hexanes) to give the desired productas a brown oil. LCMS calculated for C₃₂H₄₂FN₆O₃ (M+H)⁺: m/z=577.3;Found: 577.3.

Step 2.N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-(2-methylpiperidin-1-yl)cinnoline-8-carboxamide

The compound from the previous step was treated with 1:1 DCM/TFA (2 mL)for 1 h. The volatiles waere removed in vacuo and the residue wasdissolved in methanol and purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min) to give the desired product as a yellow solid(1.2 mg, 7% over 2 steps). LCMS calculated for C₂₇H₃₄FN₆O (M+H)⁺:m/z=477.3; Found: 477.3.

Example 94N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(3R)-3-methylmorpholin-4-yl]cinnoline-8-carboxamide

This compound was prepared according to the procedure described inExample 93, using (3R)-3-methylmorpholine, instead of 2-methylpiperidineas starting material. LCMS calculated for C₂₆H₃₂FN₆O₂ (M+H)⁺: m/z=479.3;Found: 479.2. ^(i)H NMR (600 MHz, DMSO) δ 12.83 (s, 1H), 9.49 (s, 1H),8.51 (d, J=5.4 Hz, 1H), 8.37 (dd, J=8.0, 5.8 Hz, 1H), 8.00 (m, 2H), 7.66(m, 1H), 7.62 (s, 1H), 7.58 (d, J=5.4 Hz, 1H), 4.70 (dd, J=6.7, 2.3 Hz,1H), 4.14-4.05 (m, 2H), 3.87 (d, J=11.3 Hz, 1H), 3.79 (m, 1H), 3.64 (m,1H), 3.39-3.29 (m, 3H), 2.12 (d, J=11.7 Hz, 1H), 2.03 (m, 2H), 1.90 (d,J=12.6 Hz, 1H), 1.54 (m, 1H), 1.28 (d, J=6.7 Hz, 3H), 1.17 (m, 2H), 1.02(d, J=6.4 Hz, 3H).

Example 95N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(2R)-2-methylpyrrolidin-1-yl]cinnoline-8-carboxamide

This compound was prepared according to the procedure described inExample 93, using (2R)-2-methylpyrrolidine, instead of2-methylpiperidine as starting material. LCMS calculated for C₂₆H₃₂FN₆O(M+H)⁺: m/z=463.3; Found: 463.3.^(C) ₁₋₆1-INMR (500 MHz, dmso) δ 13.00(s, 1H), 9.56 (s, 1H), 8.49 (d, J=5.4 Hz, 1H), 8.29 (dd, J=8.1, 5.9 Hz,1H), 7.96 (s, 2H), 7.62-7.54 (m, 2H), 7.16 (s, 1H), 4.47-4.40 (m, 1H),3.70 (t, J=8.3 Hz, 1H), 3.45 (m, 2H), 3.33 (t, J=12.1 Hz, 1H), 2.24-2.03(m, 7H), 1.91-1.80 (m, 2H), 1.51 (q, J=12.1 Hz, 1H), 1.28 (d, J=6.3 Hz,3H), 1.16 (m, 2H), 1.01 (d, J=6.5 Hz, 3H).

Example 96N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2-azabicyclo[2.2.1]heptan-2-yl)-5-fluoroquinoline-8-carboxamide

tert-Butyl (1S, 3R,5S)-3-(3-(5-fluoro-3-iodoquinoline-8-carboxamido)pyridin-4-yl)-5-methylcyclohexylcarbamate(20 mg, 0.03 mmol, Intermediate 1), cesium carbonate (29 mg, 0.09 mmol),RuPhos Pd G2 (5 mg, 0.006 mmol, Sigma-Aldrich) and a magnet bar wereplaced in a vial which was then evacuated and backfilled with nitrogenthree times. Then 1,4-dioxane (2 mL) and 2-azabicyclo[2.2.1]heptane (6μL, 0.06 mmol) were added. The reaction was stirred at 80° C. overnight.At this time the reaction was quenched by the addition of water and theproduct was extracted with ethyl acetate. Combined organic fractionswere washed with brine, dried over sodium sulfate and the solvents wereevaporated under reduced pressure. Trifluoroacetic acid (1 mL) anddichloromethane (1 mL) were added to the obtained crude product and thereaction mixture was stirred at r.t. for 1 h. After dilution withacetonitrile and neutralization by the addition of the ammonia solution,the desired product was purified by RP-HPLC (water XBridge C18 column,30 mm×100 mm, 5 μm particle size, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).LCMS calculated for C₂₈H₃₃FN₅O (M+H)⁺ m/z=474.2; found: 474.2.

Example 97N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2-fluorophenyl)(methyl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 2-fluoro-N-methylaniline. LCMS calculated for C₂₉H₃₀F₂N₅O (M+H)⁺m/z=502.2; found: 502.2.

¹H NMR (600 MHz, DMSO-d6) δ 13.10 (s, 1H), 9.35 (s, 1H), 8.51-8.41 (m,3H), 7.93 (br, 2H), 7.74 (d, J=3.0 Hz, 1H), 7.65-7.57 (m, 2H), 7.54-7.45(m, 3H), 7.44-7.38 (m, 1H), 3.48 (s, 3H), 3.21-3.08 (m, 1H), 3.02-2.88(m, 1H), 2.01 (d, J=12.0 Hz, 1H), 1.89 (d, J=12.4 Hz, 1H), 1.80 (d,J=12.8 Hz, 1H), 1.47 (q, J=12.0 Hz, 1H), 1.36-1.22 (m, 1H), 1.14-1.06(m, 1H), 1.06-0.99 (m, 1H), 0.80 (d, J=6.5 Hz, 3H) ppm.

Example 98N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using endo-8-azabicyclo[3.2.1]octan-3-ol. LCMS calculated forC₂₉H₃₅FN₅O₂ (M+H)⁺ m/z=504.2; found: 504.2.

Example 99N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-34(R)-2,4-dimethyl-5-oxopiperazin-1-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using (R)-1,5-dimethylpiperazin-2-one. LCMS calculated for C₂₈H₃₄FN₆O₂(M+H)⁺ m/z=505.2; found: 505.2.

Example 100N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-34(R)-4-oxodihydro-1H-pyrido[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using (R)-hexahydro-1H-pyrido[1,2-a]pyrazin-4(6H)-one. LCMS calculatedfor C₃₀H₃₆FN₆O₂ (M+H)⁺ m/z=531.2; found: 531.3.

¹H NMR (600 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.24 (s, 1H), 9.07 (d, J=3.0Hz, 1H), 8.55 (d, J=5.4 Hz, 1H), 8.46 (dd, J=8.3, 6.2 Hz, 1H), 8.08-7.99(m, 2H), 7.83 (d, J=3.0 Hz, 1H), 7.63 (d, J=5.5 Hz, 1H), 7.60 (dd,J=9.4, 8.5 Hz, 1H), 4.57-4.50 (m, 1H), 4.25 (d, J=16.6 Hz, 1H), 4.11(dd, J=13.3, 3.4 Hz, 1H), 4.02 (d, J=16.7 Hz, 1H), 3.63-3.55 (m, 1H),3.39 (dd, J=13.3, 8.1 Hz, 1H), 3.33-3.16 (m, 2H), 2.54 (td, J=13.1, 2.9Hz, 1H), 2.14 (d, J=11.8 Hz, 1H), 1.99 (d, J=12.2 Hz, 1H), 1.93-1.80 (m,4H), 1.80-1.68 (m, 1H), 1.61-1.47 (m, 2H), 1.39-1.26 (m, 2H), 1.18 (q,J=12.2 Hz, 1H), 1.10 (q, J=12.1 Hz, 1H), 0.99 (d, J=6.6 Hz, 3H) ppm.

Example 101N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-methoxyazepan-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 4-methoxyazepane. LCMS calculated for C₂₉H₃₇FN₅O₂ (M+H)⁺m/z=506.2; found: 506.2.

Example 102N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(1,4-oxazepan-4-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 1,4-oxazepane. LCMS calculated for C₂₇F₃₃FN₅O₂ (M+H)⁺ m/z=478.2;found: 478.2.

¹H NMR (600 MHz, DMSO-d6) δ 13.18 (s, 1H), 9.27 (s, 1H), 8.88 (d, J=3.1Hz, 1H), 8.52 (s, 1H), 8.36 (dd, J=8.3, 6.2 Hz, 1H), 8.01 (s, 2H), 7.58(d, J=5.0 Hz, 1H), 7.56-7.49 (m, 2H), 3.86-3.78 (m, 6H), 3.70-3.63 (m,2H), 3.32-3.14 (m, 2H), 2.12 (d, J=11.9 Hz, 1H), 2.03-1.94 (m, 3H), 1.93(d, J=12.9 Hz, 1H), 1.80-1.66 (m, 1H), 1.57 (q, J=12.0 Hz, 1H),1.23-1.06 (m, 2H), 1.00 (d, J=6.6 Hz, 3H) ppm.

Example 103N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 2-azaspiro[3.3]heptan-6-ol. LCMS calculated for C₂₈H₃₃FN₅O₂ (M+H)⁺m/z=490.2; found: 490.2.

Example 104N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-hydroxyazepan-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using azepan-4-ol. LCMS calculated for C₂₈H₃₅FN₅O₂ (M+H)⁺ m/z=492.2;found: 492.3.

Example 105N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-3-methylpiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using (R)-3-methylpiperidine. LCMS calculated for C₂₈H₃₅FN₅O (M+H)⁺m/z=476.2; found: 476.2.

Example 106N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 3-oxa-9-azabicyclo[3.3.1]nonane. LCMS calculated for C₂₉H₃₅FN₅O₂(M+H)⁺ m/z=504.2; found: 504.2.

Example 107N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(2-azaspiro[3.3]heptan-2-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 2-azaspiro[3.3]heptane. LCMS calculated for C₂₈H₃₃FN₅O (M+H)⁺m/z=474.2; found: 474.2.

Example 108N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((3S,4S)-3-fluoro-4-hydroxypiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using (3S,4S)-3-fluoropiperidin-4-ol. LCMS calculated for C₂₇H₃₂F₂N₅O₂(M+H)⁺ m/z=496.2; found: 496.2.

¹H NMR (600 MHz, DMSO-d6) δ 12.95 (s, 1H), 9.17 (d, J=3.0 Hz, 1H), 9.08(s, 1H), 8.44 (dd, J=8.3, 6.2 Hz, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.77 (d,J=3.0 Hz, 1H), 7.59-7.53 (m, 1H), 7.38 (d, J=5.1 Hz, 1H), 5.40 (br, 1H),4.61-4.41 (m, 1H), 4.09-3.94 (m, 1H), 3.85-3.68 (m, 2H), 3.49-3.41 (m,1H), 3.37-3.25 (m, 1H), 2.99 (t, J=12.1 Hz, 1H), 2.80-2.65 (m, 1H),2.13-2.00 (m, 2H), 1.83 (d, J=12.7 Hz, 1H), 1.75 (d, J=12.5 Hz, 1H),1.70-1.50 (m, 2H), 1.25-1.09 (m, 2H), 0.94 (d, J=6.6 Hz, 3H), 0.81 (q,J=11.9 Hz, 1H) ppm.

Example 109N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(1,2-oxazinan-2-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 1,2-oxazinane. LCMS calculated for C₂₆H₃₁FN₅O₂ (M+H)⁺ m/z=464.2;found: 464.3.

Example 110N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(dihydro-1H-furo[3,4-c]pyrrol-5(3H,6H,6aH)-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using hexahydro-1H-furo[3,4-c]pyrrole. LCMS calculated for C₂₈H₃₃FN₅O₂(M+H)⁺ m/z=490.2; found: 490.2.

Example 111N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(3-methylazetidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 3-methylazetidine. LCMS calculated for C₂₆H₃₁FN₅O (M+H)⁺m/z=448.2; found: 448.2.

¹H NMR (600 MHz, DMSO-d6) δ 13.11 (s, 1H), 9.26 (s, 1H), 8.52 (d, J=5.1Hz, 1H), 8.46 (d, J=2.9 Hz, 1H), 8.37 (dd, J=8.3, 6.3 Hz, 1H), 8.08-7.98(m, 2H), 7.59 (d, J=5.4 Hz, 1H), 7.56-7.51 (m, 1H), 7.23 (d, J=2.8 Hz,1H), 4.24 (td, J=7.7, 2.9 Hz, 2H), 3.74-3.68 (m, 2H), 3.27-3.13 (m, 2H),2.99-2.89 (m, 1H), 2.12 (d, J=11.8 Hz, 1H), 2.01 (d, J=12.2 Hz, 1H),1.89 (d, J=12.9 Hz, 1H), 1.79-1.68 (m, 1H), 1.56 (q, J=12.1 Hz, 1H),1.32 (d, J=6.9 Hz, 3H), 1.19 (q, J=12.2 Hz, 1H), 1.11 (q, J=12.1 Hz,1H), 1.02 (d, J=6.6 Hz, 3H) ppm.

Example 112N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((5)-2,4-dimethyl-3-oxopiperazin-1-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using (S)-1,3-dimethylpiperazin-2-one. LCMS calculated for C₂₈H₃₄FN₆O₂(M+H)⁺ m/z=505.2; found: 505.2.

Example 113N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-3-methylpiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using (S)-3-methylpiperidine. LCMS calculated for C₂₈H₃₅FN₅O (M+H)⁺m/z=476.2; found: 476.2.

Example 114N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(4-cyclopropyl-3-oxopiperazin-1-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 1-cyclopropylpiperazin-2-one. LCMS calculated for C₂₉H₃₄FN₆O₂(M+H)⁺ m/z=517.2; found: 517.2.

¹H NMR (600 MHz, DMSO-d6) δ 13.03 (s, 1H), 9.22 (s, 1H), 9.00 (d, J=3.0Hz, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.44 (dd, J=8.3, 6.2 Hz, 1H), 8.05-7.98(m, 2H), 7.72 (d, J=3.0 Hz, 1H), 7.64-7.55 (m, 2H), 4.12 (d, J=1.9 Hz,2H), 3.81-3.72 (m, 2H), 3.49 (t, J=5.4 Hz, 2H), 3.30-3.10 (m, 2H),2.87-2.73 (m, 1H), 2.13 (d, J=11.9 Hz, 1H), 1.99 (d, J=12.0 Hz, 1H),1.90 (d, J=12.8 Hz, 1H), 1.81-1.70 (m, 1H), 1.53 (q, J=12.1 Hz, 1H),1.20 (q, J=12.2 Hz, 1H), 1.10 (q, J=12.1 Hz, 1H), 1.01 (d, J=6.6 Hz,3H), 0.83-0.66 (m, 5H) ppm.

Example 115N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-isopropyl-3-oxopiperazin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 1-isopropylpiperazin-2-one. LCMS calculated for C₂₉H₃₆FN₆O₂ (M+H)⁺m/z=519.2; found: 519.2.

Example 116N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(3,3-dimethylazetidin-1-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 3,3-dimethylazetidine. LCMS calculated for C₂₇F₃₃FN₅O (M+H)⁺m/z=462.2; found: 462.3.

¹H NMR (600 MHz, DMSO-d6) δ 13.08 (s, 1H), 9.24 (s, 1H), 8.51 (d, J=5.3Hz, 1H), 8.48 (d, J=2.9 Hz, 1H), 8.38 (dd, J=8.3, 6.3 Hz, 1H), 8.01 (br,2H), 7.59-7.56 (m, 1H), 7.56-7.52 (m, 1H), 7.25 (d, J=2.8 Hz, 1H), 3.84(d, J=1.8 Hz, 4H), 3.29-3.11 (m, 2H), 2.12 (d, J=11.9 Hz, 1H), 2.01 (d,J=11.9 Hz, 1H), 1.90 (d, J=12.7 Hz, 1H), 1.80-1.68 (m, 1H), 1.56 (q,J=12.0 Hz, 1H), 1.36 (s, 6H), 1.19 (q, J=12.2 Hz, 1H), 1.11 (q, J=12.1Hz, 1H), 1.02 (d, J=6.6 Hz, 3H) ppm.

Example 117N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-isobutyl-3-oxopiperazin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 1-isobutylpiperazin-2-one. LCMS calculated for C₃₀H₃₈FN₆O₂ (M+H)⁺m/z=533.3; found: 533.3.

Example 118N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(3-methoxy-3-methylazetidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 3-methoxy-3-methylazetidine. LCMS calculated for C₂₇H₃₃FN₅O₂(M+H)⁺ m/z=478.2; found: 478.2.

¹H NMR (600 MHz, DMSO-d6) δ 13.04 (s, 1H), 9.22 (s, 1H), 8.53 (d, J=2.9Hz, 1H), 8.50 (d, J=5.3 Hz, 1H), 8.39 (dd, J=8.3, 6.3 Hz, 1H), 8.05-7.98(m, 2H), 7.59-7.52 (m, 2H), 7.33 (d, J=2.8 Hz, 1H), 4.06 (t, J=8.2 Hz,2H), 3.99 (t, J=8.1 Hz, 2H), 3.26 (s, 3H), 3.24-3.10 (m, 2H), 2.12 (d,J=11.9 Hz, 1H), 2.01 (d, J=12.2 Hz, 1H), 1.89 (d, J=12.7 Hz, 1H),1.78-1.69 (m, 1H), 1.59-1.49 (m, 4H), 1.20 (q, J=12.2 Hz, 1H), 1.10 (q,J=12.1 Hz, 1H), 1.02 (d, J=6.6 Hz, 3H) ppm.

Example 119N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(2-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine. LCMScalculated for C₂₉H₃₃FN7O (M+H)⁺ m/z=514.2; found: 514.2.

Example 120N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 5-fluoro-3,4-dihydro-2H-benzo [b] [1,4]oxazine. LCMS calculatedfor C₃₀H₃₀F₂N₅O₂ (M+H)⁺ m/z=530.2; found: 530.3.

Example 121N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 7-oxa-2-azaspiro[3.5]nonane. LCMS calculated for C₂₉H₃₅FN₅O₂(M+H)⁺ m/z=504.2; found: 504.2.

Example 122N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(3-ethoxyazetidin-1-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 3-ethoxyazetidine. LCMS calculated for C₂₇H₃₃FN₅O₂ (M+H)⁺m/z=478.2; found: 478.2.

Example 123N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-2-(hydroxymethypazetidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using (S)-azetidin-2-ylmethanol. LCMS calculated for C₂₆H₃₁FN₅O₂ (M+H)⁺m/z=464.2; found: 464.2.

Example 124N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-(methylsulfonyl)-1,4-diazepan-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 1-(methylsulfonyl)-1,4-diazepane. LCMS calculated for C₂₈H₃₆FN₆O₃S(M+H)⁺ m/z=555.2; found: 555.2.

Example 125N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(2-fluorophenylamino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 2-fluoroaniline. LCMS calculated for C₂₈H₂₈F₂N₅O (M+H)⁺ m/z=488.2;found: 488.2.

Example 126 Methyl4-(8-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-ylcarbamoyl)-5-fluoroquinolin-3-yl)-1,4-diazepane-1-carboxylate

This compound was synthesized according to the procedures of Example 96,using methyl 1,4-diazepane-1-carboxylate. LCMS calculated forC₂₉H₃₆FN₆O₃ (M+H)⁺ m/z=535.2; found: 535.3.

Example 127N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(1-methyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine. LCMScalculated for C₂₉H₃₃FN₇O (M+H)⁺ m/z=514.3; found: 514.3.

Example 128N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(6-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 2-methyl-1,2,6-thiadiazinane 1,1-dioxide. LCMS calculated forC₂₆H₃₂FN₆O₃S (M+H)⁺ m/z=527.2; found: 527.2.

Example 129N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2-cyanophenylamino)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 2-aminobenzonitrile. LCMS calculated for C₂₉H₂₈FN₆O (M+H)⁺m/z=495.2; found: 495.2.

Example 130N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5′-fluoro-3,4-dihydro-2H-1,3′-biquinoline-8′-carboxamide

This compound was synthesized according to the procedures of Example 96,using 1,2,3,4-tetrahydroquinoline. LCMS calculated for C₃₁H₃₃FN₅O (M+H)⁺m/z=510.2; found: 510.2.

Example 131N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-methoxypiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 4-methoxypiperidine. LCMS calculated for C₂₈H₃₅FN₅O₂ (M+H)⁺m/z=492.2; found: 492.2.

Example 132N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(2-(hydroxymethyl)morpholino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using morpholin-2-ylmethanol. LCMS calculated for C₂₇H₃₃FN₅O₃ (M+H)⁺m/z=494.2; found: 494.2.

Example 133N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-(2-methoxyethyl)-3-oxopiperazin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 1-(2-methoxyethyl)piperazin-2-one. LCMS calculated for C₂₉H₃₆FN₆O₃(M+H)⁺ m/z=535.2; found: 535.2.

Example 134N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(5,6-dihydro-[1,2,4]triazolo [4,3-a]pyrazin-7(8H)-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine. LCMS calculatedfor C₂₇H₃₀FN80 (M+H)⁺ m/z=501.2; found: 501.2.

Example 135N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-methyl-3-oxo-1,4-diazepan-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 1-methyl-1,4-diazepan-2-one. LCMS calculated for C₂₈H₃₄FN₆O₂(M+H)⁺ m/z=505.2; found: 505.2.

Example 136N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(7-azabicyclo[2.2.1]heptan-7-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using 7-azabicyclo[2.2.1]heptane. LCMS calculated for C₂₈H₃₃FN₅O (M+H)⁺m/z=474.2; found: 474.2.

¹H NMR (600 MHz, DMSO-d6) δ 13.06 (s, 1H), 9.24 (s, 1H), 8.99 (d, J=2.9Hz, 1H), 8.53 (d, J=5.3 Hz, 1H), 8.43 (dd, J=8.3, 6.2 Hz, 1H), 8.11-8.00(m, 2H), 7.86 (d, J=2.8 Hz, 1H), 7.64-7.53 (m, 2H), 4.62 (s, 2H),3.33-3.14 (m, 2H), 2.14 (d, J=11.9 Hz, 1H), 2.00 (d, J=12.3 Hz, 1H),1.91 (d, J=12.8 Hz, 1H), 1.82-1.69 (m, 5H), 1.60-1.49 (m, 5H), 1.17 (q,J=12.2 Hz, 1H), 1.10 (q, J=12.1 Hz, 1H), 1.00 (d, J=6.6 Hz, 3H) ppm.

Example 137N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5′,8-difluoro-3,4-dihydro-2H-1,3′-biquinoline-8′-carboxamide

This compound was synthesized according to the procedures of Example 96,using 8-fluoro-1,2,3,4-tetrahydroquinoline. LCMS calculated forC₃₁H₃₂F₂N₅O (M+H)⁺ m/z=528.2; found: 528.2.

Example 138N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(1,1-dioxidoisothiazolidin-2-yl)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using isothiazolidine 1,1-dioxide. LCMS calculated for C₂₅H₂₉FN₅O₃S(M+H)⁺ m/z=498.2; found: 498.2.

Example 139N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((3-(difluoromethoxy)pyridin-2-yl)(methyl)amino)-5-fluoroquinoline-8-carboxamide

Step 1. Methyl3-{[3-(difluoromethoxy)pyridin-2-yl]amino}-5-fluoroquinoline-8-carboxylate

Methyl 5-fluoro-3-iodoquinoline-8-carboxylate (200 mg, 0.6 mmol), cesiumcarbonate (590 mg, 1.8 mmol), 3-(difluoromethoxy)pyridin-2-amine (120mg, 0.78 mmol), RuPhos Pd G2 (70. mg, 0.09 mmol, Sigma-Aldrich) and amagnet bar were placed in a vial which was then evacuated and backfilledwith nitrogen three times. Then 1,4-dioxane (8 mL) was added. Thereaction mixture was stirred at 80° C. overnight. At this time thereaction was quenched by the addition of water and the product wasextracted with ethyl acetate. Combined organic fractions were washedwith brine, dried over sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure to give the crude product which wasused in the next step without further purification. LCMS calculated forC₁₇H₁₃F₃N₃O₃ (M+H)⁺ m/z=364.1; found: 364.1.

Step 2. Methyl3-[[3-(difluoromethozy)pyridin-2-yl](methyl)amino]-5-fluoroquinoline-8-carboxylate

NaH in mineral oil (29 mg, 0.72 mmol) was slowly added to a mixture ofmethyl 3-{[3-(difluoromethoxy)pyridin-2-yl]amino}-5-fluoroquinoline-8-carboxylate (from previous step) and methyliodide (0.11 mL, 1.8 mmol) in N,N-dimethylformamide (1.51 mL). Afterstirring at r.t. for 1 h, the reaction was quenched with water. Themixture was extracted with ethyl acetate. Combined organic fractionswere washed with brine, dried over sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. Crude material waspurified by Biotage Isolera™ (flash purification system withhexane/ethyl acetate at a ratio from 0 to 100%) to give the desiredproduct (211 mg, 93% over two steps). LCMS calculated for C₁₈H₁₅F₃N₃O₃(M+H)⁺ m/z=378.1; found: 378.1.

Step 3.3-[[3-(difluoromethozy)pyridin-2-yl](methyl)amino]-5-fluoroquinoline-8-carboxylicacid

A 1 M solution of sodium hydroxide in water (2.2 mL, 2.2 mmol) was addedto a solution of methyl3-3-(difluoromethoxy)pyridin-2-yl](methyl)amino]-5-fluoroquinoline-8-carboxylate(211 mg, 0.559 mmol) in tetrahydrofuran (6 mL) and methanol (4 mL).After stirring at r.t. for 2 h, pH was adjusted to 5 by the addition ofa 1 M solution of HCl. The product was then extracted with ethyl acetateand the organic phase was washed with brine. The organic phase was driedover sodium sulfate and filtered. The filtrate was concentrated underreduced pressure. The resulting crude product was used directly in thenext step without further purification (195 mg, 96%). LCMS calculatedfor C₁₇H₁₃F₃N₃O₃ (M+H)⁺ m/z=364.1; found 364.1.

Step 4.N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-[[3-(difluoromethoxy)pyridin-2-yl](methyl)amino]-5-fluoroquinoline-8-carboxamide

To a mixture of tert-butyl(1S,3R,5S)-3-(3-aminopyridin-4-yl)-5-methylcyclohexylcarbamate (15 mg,0.049 mmol) and3-[[3-(difluoromethoxy)pyridin-2-yl](methyl)amino]-5-fluoroquinoline-8-carboxylicacid (17.8 mg, 0.0491 mmol) in N,N-dimethylformamide (1.5 mL) was addedN,N-diisopropylethylamine (17 μL, 0.098 mmol) andN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (24 mg, 0.064 mmol). After stirring at r.t. for 2hours, the reaction was quenched with water. The precipitate wascollected by filtration and washed with water twice. Then it wasredissolved in ethyl acetate to give a solution which was washed withbrine, dried over sodium sulfate and filtered.

After the solvent was evaporated, trifluoroacetic acid (1 mL) anddichloromethane (1 mL) were added to the obtained crude product and thereaction mixture was stirred at r.t. for 1 h. After dilution withacetonitrile and neutralization with the ammonia solution, the desiredproduct was purified by RP-HPLC (water XBridge C18 column, 30 mm×100 mm,5 um particle size, eluting with a gradient of acetonitrile/watercontaining 0.1% NH₄OH, at flow rate of 60 mL/min). LCMS calculated forC₂₉H₃₀F₃N₆O₂ (M+H)⁺ m/z=551.2; found: 551.3.

Example 140N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((2-cyanocyclopentyl)(methyl)amino)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using 2-aminocyclopentanecarbonitrile. LCMS calculated forC₂₉H₃₄FN₆O (M+H)⁺ m/z=501.3; found: 501.3.

Example 141N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-02,6-dimethylpyridin-3-yl)(methyl)amino)-5-fluoroquinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using 2,6-dimethylpyridin-3-amine. LCMS calculated for C₃₀H₃₄FN₆O(M+H)⁺ m/z=513.3; found: 513.3.

Example 142N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((3-fluoropyridin-2-yl)(methyl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using 3-fluoropyridin-2-amine. LCMS calculated for C₂₈H₂₉F₂N₆O(M+H)⁺ m/z=503.2; found: 503.2.

Example 143N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl(4-(trifluoromethyl)pyridin-3-yl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using 4-(trifluoromethyl)pyridin-3-amine. LCMS calculated forC₂₉H₂₉F₄N₆O (M+H)⁺ m/z=553.2; found: 553.2.

Example 144N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((6-methoxy-2-methylpyridin-3-yl)(methyl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using 6-methoxy-2-methylpyridin-3-amine. LCMS calculated forC₃₀H₃₄FN₆O₂ (M+H)⁺ m/z=529.3; found: 529.2.

Example 145N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((3-fluoropyridin-4-yl)(methyl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using 3-fluoropyridin-4-amine. LCMS calculated for C₂₈H₂₉F₂N₆O(M+H)⁺ m/z=503.2; found: 503.2.

Example 146N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl(4-methylpyridin-3-yl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using 4-methylpyridin-3-amine. LCMS calculated for C₂₉H₃₂FN₆O(M+H)⁺ m/z=499.2; found: 499.2.

Example 147N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl(2-methylcyclobutyl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using 2-methylcyclobutanamine. LCMS calculated for C₂₈H₃₅FN₅O(M+H)⁺ m/z=476.3; found: 476.3.

Example 148N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((4-methoxyphenyl)(methyl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using 4-methoxyaniline. LCMS calculated for C₃₀H₃₃FN₅O₂ (M+H)⁺m/z=514.3; found: 514.3.

Example 149N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl(3-methylpyrazin-2-yl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using 3-methylpyrazin-2-amine. LCMS calculated for C₂₈H₃₁FN₇O(M+H)⁺ m/z=500.3; found: 500.3.

Example 150N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((4-methoxypyridin-3-yl)(methyl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using 4-methoxypyridin-3-amine. LCMS calculated for C₂₉H₃₂FN₆O₂(M+H)⁺ m/z=515.3; found: 515.3.

Example 151N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyhtetrahydro-2H-pyran-3-yl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using tetrahydro-2H-pyran-3-amine. LCMS calculated for C₂₈H₃₅FN₅O₂(M+H)⁺ m/z=492.3; found: 492.3.

Example 152N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2-methoxyphenyl)(methyl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using 2-methoxyaniline. LCMS calculated for C₃₀H₃₃FN₅O₂ (M+H)⁺m/z=514.3; found: 514.3.

Example 153N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(imidazo[1,2-a]pyridin-6-yl(methyl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using imidazo[1,2-a]pyridin-6-amine. LCMS calculated for C₃₀H₃₁FN₇O(M+H)⁺ m/z=524.3; found: 524.2.

Example 154N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl((R)-tetrahydrofuran-3-yl)amino)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example139, using (R)-tetrahydrofuran-3-amine. LCMS calculated for C₂₇H₃₃FN₅O₂(M+H)⁺ m/z=478.3; found: 478.2.

Example 155N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(2S,4R)-4-methoxy-2-methylpyrrolidin-1-yl]quinoline-8-carboxamide

Step 1. tert-Butyl (2S, 4R)-4-methoxy-2-methylpyrrolidine-1-carboxylate

NaH in mineral oil (43 mg, 1.8 mmol) was slowly added to a mixture oftert-butyl (2S,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (300 mg,1.5 mmol) and methyl iodide (280 μL, 4.5 mmol) in N,N-dimethylformamide(5 mL). After stirring at r.t. for 1 h, the reaction was quenched withwater. The mixture was extracted with ethyl acetate. Combined organicfractions were washed with brine, dried over sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure. Crudematerial was purified by Biotage Isolera (flash purification system withhexane/ethyl acetate at a ratio from 0 to 100%) to give the desiredproduct (297 mg, 92%). LCMS calculated for C₇H₁₄NO₃ (M-tBu+H)⁺m/z=160.1; found: 160.1.

Step 2. (2S,4R)-4-Methoxy-2-methylpyrrolidine hydrochloride

A 4.0M solution of hydrogen chloride in dioxane (3 mL, 10 mmol) wasadded to a solution of tert-butyl (2S,4R)-4-methoxy-2-methylpyrrolidine-1-carboxylate (297 mg, 1.4 mmol) inmethanol (2 mL). After stirring at r.t. for 1 h, the reaction wasconcentrated under reduced pressure to give the HCl salt of the desiredproduct which was used directly in the next step without furtherpurification. LCMS calculated for C₆H₁₄NO (M+H)⁺ m/z=116.1; found:116.1.

Step 3.N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(2S,4R)-4-methoxy-2-methylpyrrolidin-1-yl]quinoline-8-carboxamide

tert-Butyl(1S,3R,5S)-3-(3-(5-fluoro-3-iodoquinoline-8-carboxamido)pyridin-4-yl)-5-methylcyclohexylcarbamate(20 mg, 0.03 mmol, Intermediate 1),(2S,4R)-4-methoxy-2-methylpyrrolidine hydrochloride (10 mg, 0.06 mmol),cesium carbonate (29 mg, 0.09 mmol), RuPhos Pd G2 (5 mg, 0.006 mmol,Sigma-Aldrich) and a magnet bar were placed in a vial which was thenevacuated and backfilled with nitrogen three times. Then 1,4-dioxane (2mL) was added. The reaction was stirred at 80° C. overnight. Aftercooling to room temperature, the reaction was quenched with water. Themixture was extracted with ethyl acetate. Combined organic fractionswere washed with brine, dried over sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure. Trifluoroacetic acid(1 mL) and dichloromethane (1 mL) were added to the obtained crudeproduct and the reaction mixture was stirred at r.t. for 1 h. Afterdilution with acetonitrile and neutralization with ammonia solution, thedesired product was purified by RP-HPLC (water XBridge C18 column, 30mm×100 mm, 5 μm particle size, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).LCMS calculated for C₂₈H₃₅FN₅O₂ (M+H)⁺ m/z=492.3; found: 492.2.

¹H NMR (600 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.28 (s, 1H), 8.73 (d, J=2.9Hz, 1H), 8.50 (d, J=5.3 Hz, 1H), 8.36 (dd, J=8.2, 6.2 Hz, 1H), 7.96 (br,2H), 7.60-7.46 (m, 2H), 7.33 (d, J=2.9 Hz, 1H), 4.25 (p, J=6.5 Hz, 1H),4.18 (t, J=5.1 Hz, 1H), 3.70 (d, J=11.2 Hz, 1H), 3.61 (dd, J=11.2, 5.1Hz, 1H), 3.35 (s, 3H), 3.32-3.19 (m, 2H), 2.34-2.25 (m, 1H), 2.12 (d,J=11.9 Hz, 1H), 2.06-1.98 (m, 2H), 1.94 (d, J=12.7 Hz, 1H), 1.85-1.72(m, 1H), 1.59 (q, J=12.0 Hz, 1H), 1.34 (d, J=6.3 Hz, 3H), 1.21-1.13 (m,1H), 1.13-1.06 (m, 1H), 1.01 (d, J=6.6 Hz, 3H) ppm.

Example 156N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-02R,4R)-4-methoxy-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example155, using (2R,4R)-tert-butyl4-hydroxy-2-methylpyrrolidine-1-carboxylate. LCMS calculated forC₂₈H₃₅FN₅O₂ (M+H)³⁰ m/z=492.3; found: 492.3.

Example 157N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2S,4S)-4-methoxy-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example155, using (2S,4S)-tert-butyl4-hydroxy-2-methylpyrrolidine-1-carboxylate. LCMS calculated forC₂₈H₃₅FN₅O₂ (M+H)⁺ m/z=492.3; found: 492.3.

Example 158 N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2R,4S)-4-methoxy-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example155, using (2R,4S)-tert-butyl4-hydroxy-2-methylpyrrolidine-1-carboxylate. LCMS calculated forC₂₈H₃₅FN₅O₂ (M+H)⁺ m/z=492.3; found: 492.3.

¹H NMR (600 MHz, DMSO-d6) δ 13.25 (s, 1H), 9.32 (s, 1H), 8.67 (d, J=3.0Hz, 1H), 8.58-8.47 (m, 1H), 8.34 (dd, J=8.2, 6.2 Hz, 1H), 8.02 (br, 2H),7.61 (d, J=5.3 Hz, 1H), 7.51 (dd, J=9.6, 8.4 Hz, 1H), 7.28 (d, J=2.9 Hz,1H), 4.24 (p, J=6.7 Hz, 1H), 4.18 (t, J=5.1 Hz, 1H), 3.69 (d, J=11.2 Hz,1H), 3.57 (dd, J=11.3, 5.1 Hz, 1H), 3.34 (s, 3H), 3.28-3.12 (m, 2H),2.33-2.25 (m, 1H), 2.11 (d, J=11.9 Hz, 1H), 2.04 (d, J=13.2 Hz, 1H),2.00 (d, J=12.4 Hz, 1H), 1.94 (d, J=12.7 Hz, 1H), 1.83-1.73 (m, 1H),1.55 (q, J=12.0 Hz, 1H), 1.34 (d, J=6.3 Hz, 3H), 1.21 (q, J=12.1 Hz,1H), 1.12 (q, J=12.1 Hz, 1H), 1.05 (d, J=6.5 Hz, 3H) ppm.

Example 159N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2R,4S)-4-methoxy-2-methylpiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example155, using (2R,4S)-tert-butyl4-hydroxy-2-methylpiperidine-1-carboxylate. LCMS calculated forC₂₉H₃₇FN₅O₂ (M+H)⁺ m/z=506.3; found: 506.3.

¹H NMR (600 MHz, DMSO-d6) δ 13.17 (s, 1H), 9.25 (s, 1H), 9.05 (d, J=3.0Hz, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.40 (dd, J=8.3, 6.2 Hz, 1H), 8.17-8.07(m, 2H), 7.70-7.63 (m, 2H), 7.55 (dd, J=9.5, 8.5 Hz, 1H), 4.67-4.57 (m,1H), 3.88-3.77 (m, 1H), 3.70-3.56 (m, 1H), 3.30 (s, 3H), 3.26-3.16 (m,2H), 3.13 (td, J=12.8, 2.9 Hz, 1H), 2.23-2.17 (m, 1H), 2.14 (d, J=11.7Hz, 1H), 2.07-2.02 (m, 1H), 1.98 (d, J=12.4 Hz, 1H), 1.90 (d, J=12.8 Hz,1H), 1.77-1.67 (m, 1H), 1.62 (td, J=12.2, 5.3 Hz, 1H), 1.56 (q, J=12.0Hz, 1H), 1.41 (qd, J=12.4, 4.8 Hz, 1H), 1.18 (q, J=12.2 Hz, 1H), 1.13(d, J=6.9 Hz, 3H), 1.12-1.06 (m, 1H), 0.99 (d, J=6.6 Hz, 3H) ppm.

Example 160N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2S,4R)-4-methoxy-2-methylpiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example155, using (2S,4R)-tert-butyl4-hydroxy-2-methylpiperidine-1-carboxylate. LCMS calculated forC₂₉H₃₇FN₅O₂ (M+H)⁺ m/z=506.3; found: 506.3.

Example 161N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2R,4R)-4-methoxy-2-methylpiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example155, using (2R,4R)-tert-butyl4-hydroxy-2-methylpiperidine-1-carboxylate. LCMS calculated forC₂₉H₃₇FN₅O₂ (M+H)⁺ m/z=506.3; found: 506.3.

¹H NMR (500 MHz, dmso-d6) δ 13.23 (s, 1H), 9.32 (s, 1H), 8.97 (d, J=2.9Hz, 1H), 8.58 (d, J=5.5 Hz, 1H), 8.42 (dd, J=8.3, 6.2 Hz, 1H), 8.04 (br,2H), 7.78-7.66 (m, 2H), 7.55 (dd, J=9.5, 8.5 Hz, 1H), 4.28-4.17 (m, 1H),3.58 (p, J=4.0 Hz, 1H), 3.51 (dt, J=12.5, 4.3 Hz, 2H), 3.31 (s, 3H),3.29-3.12 (m, 2H), 2.12 (d, J=12.1 Hz, 1H), 2.03-1.82 (m, 6H), 1.79-1.68(m, 1H), 1.57 (q, J=12.0 Hz, 1H), 1.22 (d, J=6.7 Hz, 3H), 1.20-1.15 (m,1H), 1.11 (q, J=12.1 Hz, 1H), 1.00 (d, J=6.6 Hz, 3H) ppm.

Example 162N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((3R,4R)-3-fluoro-4-methoxypiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example155, using (3R, 4R)-tert-butyl3-fluoro-4-hydroxypiperidine-1-carboxylate. LCMS calculated forC₂₈H₃₄F₂N₅O₂ (M+H)⁺ m/z=510.3; found: 510.2.

Example 163N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((3S,4S)-3-fluoro-4-(2-methoxyethoxy)piperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example155, using (3S,4S)-tert-butyl 3-fluoro-4-hydroxypiperidine-1-carboxylateand 1-iodo-2-methoxyethane. LCMS calculated for C₃₀H₃₈F₂N₅O₃ (M+H)⁺m/z=554.3; found: 554.2.

¹H NMR (600 MHz, DMSO-d6) δ 12.95 (s, 1H), 9.13 (s, 1H), 9.08 (d, J=3.0Hz, 1H), 8.50 (d, J=5.3 Hz, 1H), 8.44 (dd, J=8.3, 6.2 Hz, 1H), 7.89 (br,2H), 7.82 (d, J=3.0 Hz, 1H), 7.63-7.55 (m, 1H), 7.52 (d, J=5.4 Hz, 1H),4.79-4.61 (m, 1H), 4.04-3.94 (m, 1H), 3.78-3.66 (m, 4H), 3.55-3.46 (m,3H), 3.37-3.30 (m, 1H), 3.28 (s, 3H), 3.25-3.14 (m, 2H), 2.18-2.08 (m,2H), 1.97 (d, J=12.0 Hz, 1H), 1.91 (d, J=12.7 Hz, 1H), 1.79-1.65 (m,2H), 1.51 (q, J=12.0 Hz, 1H), 1.18 (q, J=12.2 Hz, 1H), 1.08 (q, J=12.0Hz, 1H), 1.01 (d, J=6.6 Hz, 3H) ppm.

Example 164N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(2R,4S)-4-hydroxy-2-methylpyrrolidin-1-yl]quinoline-8-carboxamide

Step 1. (3S,5R)-5-Methylpyrrolidin-3-ol hydrochloride

A 4.0M solution of hydrogen chloride in dioxane (3 mL, 10 mmol) wasadded to a solution of tert-butyl (2R,4S)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (0.30 g, 1.5 mmol) inmethanol (2 mL). After stirring at r.t. for 1 h, the reaction wasconcentrated under reduced pressure to give the HCl salt of the desiredproduct which was used directly in the next step without furtherpurification. LCMS calculated for C₅H₁₂NO (M+H)⁺ m/z=102.1; found:102.1.

Step 2.N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(2R,4S)-4-hydroxy-2-methylpyrrolidin-1-yl]quinoline-8-carboxamide

tert-Butyl (1S, 3R,5S)-3-(3-(5-fluoro-3-iodoquinoline-8-carboxamido)pyridin-4-yl)-5-methylcyclohexylcarbamate(20 mg, 0.03 mmol, Intermediate 1), (3S,5R)-5-methylpyrrolidin-3-olhydrochloride (8 mg, 0.06 mmol), cesium carbonate (29 mg, 0.09 mmol),RuPhos Pd G2 (5 mg, 0.006 mmol, Sigma-Aldrich) and a magnet bar wereplaced in a vial which was then evacuated and backfilled with nitrogenthree times. Then 1,4-dioxane (2 mL) was added. The reaction was stirredat 80° C. overnight. After cooling to room temperature, the reaction wasquenched with water. The mixture was extracted with ethyl acetate.Combined organic fractions were washed with brine, dried over sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure. Trifluoroacetic acid (1 mL) and dichloromethane (1 mL) wereadded to the obtained crude product and the reaction mixture was stirredat r.t. for 1 h. After dilution with acetonitrile and neutralizationwith ammonia solution, the desired product was purified by RP-HPLC(water XBridge C18 column, 30 mm×100 mm, 5 μm particle size, elutingwith a gradient of acetonitrile/water containing 0.1% NH₄OH, at flowrate of 60 mL/min). LCMS calculated for C₂₇H₃₃FN₅O₂ (M+H)⁺ m/z=478.3;found: 478.3.

Example 165N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example164, using (2S, 4S)-tert-butyl4-hydroxy-2-methylpyrrolidine-1-carboxylate. LCMS calculated forC₂₇H₃₃FN₅O₂ (M+H)⁺ m/z=478.3; found: 478.3.

Example 166N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-2-methylazetidin-1-yl)quinoline-8-carboxamide

Step 1. (R)-tert-Butyl2-((methylsulfonyloxy)methyl)azetidine-1-carboxylate

Methanesulfonyl chloride (1.0 mL, 13 mmol) was slowly added at 0° C. toa mixture of tert-butyl (2R)-2-(hydroxymethyl)azetidine-1-carboxylate(2.0 g, 11 mmol) and triethylamine (2.1 mL, 15 mmol) in methylenechloride (10 mL). After stirring at r.t. overnight, the reaction wasquenched with a saturated solution of sodium bicarbonate. The mixturewas extracted with DCM. Combined organic fractions were washed withbrine, dried over sodium sulfate and filtered. The filtrate wasconcentrated under reduced pressure. The resulting residue was purifiedby Biotage Isolera™ (flash purification system with hexane/ethyl acetateat a ratio from 0 to 100%) to give the desired product (2.6 g, 90%).LCMS calculated for C₆H₁₂NO₅S (M-tBu+H)⁺ m/z=210.0; found: 210.1.

Step 2. (S)-tert-Butyl 2-methylazetidine-1-carboxylate

A 1.0 M solution of lithium triethylborohydride in THF (37 mL, 37 mmol)was added dropwise at 0° C. to a solution of tert-butyl(2R)-2-{[(methylsulfonyl)oxy]methyl}azetidine-1-carboxylate (2.6 g, 9.8mmol) in tetrahydrofuran (20 mL). After stirring at r.t. for 1 h, thereaction was quenched with a saturated solution of sodium bicarbonateand the mixture was extracted with DCM. Combined organic fractions werewashed with brine, dried over sodium sulfate and filtered. The filtratewas concentrated under reduced pressure. The resulting residue waspurified by Biotage Isolera (flash purification system with hexane/ethylacetate at a ratio from 0 to 100%) to give the desired product (0.8 g,48%). LCMS calculated for C₅H₁₀NO₂ (M-tBu+H)⁺ m/z=116.1; found: 116.1.

Step 3. (S)-2-Methylazetidine

A 4.0 M solution of hydrogen chloride in dioxane (5 mL, 20 mmol) wasadded to a solution of tert-butyl (2S)-2-methylazetidine-1-carboxylate(0.80 g, 4.7 mmol) in methanol (5 mL). After stirring at r.t. for 1 h,the reaction was concentrated under reduced pressure to give the HClsalt of the desired product which was used in the next step withoutfurther purification. LCMS calculated for C₄H₁₀N (M+H)⁺ m/z=72.1; found:72.1.

Step 4.N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-2-methylazetidin-1-yl)quinoline-8-carboxamide

tert-Butyl (1S, 3R,5S)-3-(3-(5-fluoro-3-iodoquinoline-8-carboxamido)pyridin-4-yl)-5-methylcyclohexylcarbamate(20 mg, 0.03 mmol, Intermediate 1), (2S)-2-methylazetidine hydrochloride(7 mg, 0.06 mmol), cesium carbonate (29 mg, 0.09 mmol), RuPhos Pd G2 (5mg, 0.006 mmol, Sigma-Aldrich) and a magnet bar were placed in a vialwhich was then evacuated and backfilled with nitrogen three times. Then1,4-dioxane (2 mL) was added. The reaction was stirred at 80° C.overnight. After cooling to room temperature, the reaction was quenchedwith water and the mixture was extracted with ethyl acetate. Combinedorganic fractions were washed with brine, dried over sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure.Trifluoroacetic acid (1 mL) and dichloromethane (1 mL) were added to theobtained crude product and the reaction mixture was stirred at r.t. for1 h. After dilution with acetonitrile and neutralization with ammoniasolution, the desired product was purified by RP-HPLC (water XBridge C18column, 30 mm×100 mm, 5 μm particle size, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).LCMS calculated for C₂₆H₃₁FN₅O (M+H)⁺ m/z=448.2; found: 448.2.

Example 167N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-2-methylazetidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example166, using (S)-tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate. LCMScalculated for C₂₆H₃₁FN₅O (M+H)⁺ m/z=448.2; found: 448.2.

Example 168 Ethyl 4-(8-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-ylcarbamoyl)-5-fluoroquinolin-3-yl)piperazine-1-carboxylate

This compound was synthesized according to the procedures of Example 96,using ethyl piperazine-1-carboxylate. LCMS calculated for C₂₉H₃₆FN₆O₃(M+H)⁺ m/z=535.3; found: 535.3.

¹H NMR (600 MHz, DMSO-d6) δ 12.97 (s, 1H), 9.16 (s, 1H), 9.08 (d, J=3.0Hz, 1H), 8.51 (d, J=4.8 Hz, 1H), 8.46 (dd, J=8.3, 6.2 Hz, 1H), 7.92 (br,2H), 7.79 (d, J=2.9 Hz, 1H), 7.65-7.58 (m, 1H), 7.58-7.54 (m, 1H), 4.10(q, J=7.1 Hz, 2H), 3.68-3.58 (m, 4H), 3.52-3.40 (m, 4H), 3.25-3.12 (m,2H), 2.13 (d, J=12.3 Hz, 1H), 1.98 (d, J=12.2 Hz, 1H), 1.89 (d, J=12.8Hz, 1H), 1.79-1.65 (m, 1H), 1.50 (q, J=12.1 Hz, 1H), 1.23 (t, J=7.1 Hz,3H), 1.21-1.16 (m, 1H), 1.08 (q, J=12.0 Hz, 1H), 1.00 (d, J=6.6 Hz, 3H)ppm.

Example 169.N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-2-methylpiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using (R)-2-methylpiperidine. LCMS calculated for C₂₈H₃₅FN₅O (M+H)⁺m/z=476.3; found: 476.2.

¹H NMR (600 MHz, DMSO-d6) δ 13.15 (s, 1H), 9.22 (s, 1H), 9.02 (d, J=3.0Hz, 1H), 8.54 (d, J=5.4 Hz, 1H), 8.41 (dd, J=8.3, 6.2 Hz, 1H), 7.99 (s,2H), 7.65 (d, J=3.0 Hz, 1H), 7.61 (d, J=5.4 Hz, 1H), 7.56 (dd, J=9.5,8.4 Hz, 1H), 4.53-4.40 (m, 1H), 3.72-3.62 (m, 1H), 3.29-3.16 (m, 2H),3.08 (td, J=12.2, 3.0 Hz, 1H), 2.11 (d, J=11.9 Hz, 1H), 1.98 (d, J=12.2Hz, 1H), 1.93 (d, J=12.9 Hz, 1H), 1.90-1.80 (m, 2H), 1.78-1.65 (m, 3H),1.65-1.50 (m, 3H), 1.18 (q, J=12.1 Hz, 1H), 1.13 (d, J=6.7 Hz, 3H),1.10-1.05 (m, 1H), 1.01 (d, J=6.6 Hz, 3H) ppm.

Example 170N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-2-methylpiperidin-1-yl)quinoline-8-carboxamide

This compound was synthesized according to the procedures of Example 96,using (S)-2-methylpiperidine. LCMS calculated for C₂₈H₃₅FN₅O (M+H)⁺m/z=476.3; found: 476.2.

Example A Pim Enzyme Assays

Pim-1 and Pim-3 kinase assays-20 μL reactions were run in white 384 wellpolystyrene plates dotted with 0.8 μL compound/DMSO in the assay buffer(50 mM Tris, pH 7.5, 0.01% Tween-20, 5 mM mgCl₂, 0.01% BSA, 5 mM DTT),containing 0.05 μM Biotin-labeled BAD peptide substrate (AnaSpec 62269),1 mM ATP, and 2.5 pM (Pim-1, Invitrogen PV3503) or 1.25 pM (Pim-3,Millipore 1-4-738) enzyme for 1 h at 25° C. Reactions were stopped byaddition of 10 μL STOP Buffer (150 mM Tris, pH=7.5, 150 mM NaCl, 75 mMEDTA, 0.01% Tween-20, 0.3% BSA,) supplemented with Phospho-Bad (Ser112)Antibody (Cell Signaling 9291) diluted 666-fold, and Streptavidin donorbeads (PerkinElmer 6760002) along with Protein-A acceptor beads(PerkinElmer 6760137) at 15 μg/mL each. Supplementation of the STOPbuffer with beads and stopping the reactions were done under reducedlight. Prior to the stopping reactions STOP buffer with beads waspreincubated for 1 h in the dark at room temperature. After stopping thereactions, plates were incubated for 1 h in the dark at room temperaturebefore reading on a PHERAstar FS plate reader (BMG Labtech) underreduced light.

Pim-2 kinase assay-20 μL reactions were run in white 384 wellpolystyrene plates dotted with 0.8 μL compound/DMSO in the assay buffer(50 mM Tris, pH 7.5, 0.01% Tween-20, 5 mM mgCl₂, 0.01% BSA, 5 mM DTT),containing 0.05 μM Fluorescein-labeled CREBtide peptide substrate(Invitrogen PV3508), 1 mM ATP, and 1 nM enzyme (Invitrogen PV3649) for 2h at 25° C. Reactions were stopped by addition of 10 μL TR-FRET DilutionBuffer (Invitrogen PV3574) with 30 mM EDTA and 1.5 nM LanthaScreenTb-CREB pSer133 antibody (Invitrogen PV3566). After 30 min. incubationat room temperature, plates were read on a PHERAstar FS plate reader(BMG Labtech).

Compounds of the invention having an IC₅₀ of 2 μM or less when testedfor PIM kinase activity under the assay conditions disclosed above areconsidered active.

Although the above in vitro assays are conducted at 1 mM ATP compoundscan also be evaluated for potency and in vitro activity against PIMtargets utilizing K_(m) conditions, where the concentration of ATP isset to the K_(m) value and the assay is more sensitive to PIM inhibitionactivity.

Data obtained for the Example compounds using the methods described inExample A, is provided in Table 1.

TABLE 1 PIM1 IC₅₀ PIM2 IC₅₀ PIM3 IC₅₀ Example (nM)^(a) (nM)^(b) (nM)^(a)1 * ++ * 2 * + * 3 * ++ ** 4 * ++ ** 5 * + * 6 * + * 7 * + * 8 * + * 9 *++ * 10 * ++ * 11 * ++ * 12 * ++ * 13 * + * 14 * ++ * 15 * + * 16 * + *17 * ++ * 18 * + * 19 * ++ * 20 * + * 21 * + * 22 * + * 23 * ++ * 24 *++ * 25 * + * 26 * + * 27 * + * 28 * + * 29 * + * 30 * ++ * 31 * ++ *32 * + * 33 * + * 34 * + * 35 * +++ ** 36 * ++ ** 37 * +++ ** 38 * ++ **39 * + ** 40 * ++ * 41 ** ++ ** 42 * + * 43 * + * 44 * ++ * 45 * ++ **46 * ++ * 47 * + * 48 * ++ * 49 * ++ * 50 * + * 51 * ++ * 52 * +++ **53 * ++ * 54 * ++ * 55 * + * 56 * + * 57 * + ** 58 * + * 59 * +++ **60 * +++ ** 61 * +++ ** 62 * ++ * 63 * ++ * 64 * ++ * 65 * ++ * 66 *++ * 67 * + * 68 * + * 69 * + * 70 * ++ * 71 * ++ * 72 * ++ * 73 * + *74 * ++ * 75 * + * 76 * + * 77 * + * 78 * ++ * 79 * ++ * 80 * + *81 * + * 82 * ++ * 83 * + * 84 * ++ * 85 * ++ * 86 * + * 87 * ++ *88 * + * 89 * + * 90 * + * 91 * +++ ** 92 * +++ ** 93 * + * 94 * + *95 * + * 96 * + * 97 * + * 98 * + * 99 * + * 100 * + * 101 * + *102 * + * 103 * + * 104 * + * 105 * + * 106 * + * 107 * + * 108 * + *109 * + * 110 * + * 111 * + * 112 * + * 113 * + * 114 * + * 115 * + *116 * + * 117 * + * 118 * + * 119 * + * 120 * + * 121 * + * 122 * + *123 * + * 124 * + * 125 * + * 126 * + * 127 * + * 128 * + * 129 * ++ *130 * ++ * 131 * ++ * 132 * ++ * 133 * ++ * 134 * ++ * 135 * ++ *136 * + * 137 * + * 138 * ++ * 139 * + * 140 * + * 141 * + * 142 * + *143 * + * 144 * + * 145 * + * 146 * + * 147 * + * 148 * + * 149 * + *150 * + * 151 * + * 152 * + * 153 * ++ * 154 * ++ * 155 * + * 156 * + *157 * + * 158 * + * 159 * + * 160 * + * 161 * + * 162 * + * 163 * + *164 * + * 165 * + * 166 * + * 167 * + * 168 * ++ * 169 * + * 170 * ++ **^(a)IC₅₀ ≤ 10 nM: *; 10 nM < IC₅₀ ≤ 50 nM: **; 50 nM < IC₅₀ ≤ 500 nM:***; 500 nM < IC₅₀ ≤ 2000 nM: ****. ^(b)IC₅₀ ≤ 100 nM: +; 100 nM < IC₅₀≤ 1000 nM: ++; 1000 nM < IC₅₀ ≤ 10000 nM: +++.

Example B Pim Cellular Assays

One or more compounds of the invention were tested for inhibitoryactivity of PIM according to at least one of the following cellularassays. Compounds of the invention having an IC₅₀ of 10 μM or less whentested for PIM kinase activity under the cellular assay conditionsdisclosed below would be and were considered active.

Pim Cell Proliferation Assay

KG-1A cells are purchased from ATCC (Manassas, Va.) and KMS.12.BM cellsare purchased from NIBIO, JCRB cell bank (Tokyo, Japan) and maintainedin the culture mediums recommended, RPMI,10% FBS and IMDM 20% FBS(Mediatech, Manassas, Va.) respectively. To measure theanti-proliferation activity of test compounds, both cell lines areplated with the culture medium (2×10³ cells/well/in 200 μL) into 96-wellpolystyrene ultralow binding (Costar,) in the presence or absence of aconcentration range of test compounds. After 4 days, [³H]-thymidine, 1μCi/10 μL/well (PerkinElmer, Boston, Mass.) in culture medium is thenadded to the cell culture for an additional 16 h before the incorporatedradioactivity is separated by filtration with a Packard Micro plateHarvester with water through a 0.3% PEI pre wetted GF/B filter plates(Packard Bioscience/PerkinElmer, Boston, Mass.). The plate is measuredby liquid scintillation counting with a TopCount (PerkinElmer). IC₅₀determination is performed by fitting the curve of percent inhibitionversus the log of the inhibitor concentration using the GraphPad Prism5.0 software.

Pim Cell Proliferation Assay

MOLM-16 cells are purchased from DSMZ (Germany) and maintained in theculture medium recommended, RPMI,20% FBS. To measure theanti-proliferation activity of test compounds, the cells are plated withthe RPMI, 10% FBS (1×10⁴ cells/well/in 200 μL) into 96-well polystyreneultralow binding plates (Costar) in the presence or absence of aconcentration range of test compounds. After 4 days, [³H]-thymidine, 1μCi/10 μL/well (PerkinElmer, Boston, Mass.) in RPMI, 10% FBS is thenadded to the cell culture for an additional 16 h before the incorporatedradioactivity is separated by filtration with a Packard Micro plateHarvester with water through a 0.3% PEI pre wetted GF/B filter plates(Packard Bioscience/PerkinElmer, Boston, Mass.). The plate is measuredby liquid scintillation counting with a TopCount (PerkinElmer). IC₅₀determination is performed by fitting the curve of percent inhibitionversus the log of the inhibitor concentration using the GraphPad Prism5.0 software.

Pim pBAD Signaling Assays

KG-1A cells are purchased from ATCC (Manassas, Va.) and KMS.12.BM cellsare purchased from NIBIO, JCRB cell bank (Tokyo, Japan) and maintainedin the culture mediums recommended, RPMI,10% FBS and IMDM 20% FBS(Mediatech, Manassas, Va.) respectively. To measure the pBAD inhibitoryactivity of the compounds, both cell lines are plated with the culturemedium (1×10⁶/well/100 μL for KG1A and 4×10⁵ cells/well/in 100 μL forKMS12BM) into 96-well V bottom polypropylene plates (Matrix, ThermoFisher, USA) and incubated 30 min. at 37° C. to normalize cell signalingfrom handling. Test compounds are added at an appropriate concentrationrange and further incubated for 2.5 h for KMS.12.BM cells and 4 h forKG1-A cells. Plates are centrifuged at 2000 RPM for 10 min. andsupernatants aspirated. 100 μL lysis buffer with protease inhibitors(Cell Signaling Technologies, Danver, Mass., Sigma, St Louis Mo., EMD,USA) is added to the pellets, mixed well and set on ice for 30 min.Lysates are frozen overnight at −80° C. To measure the pBAD activity, aCell Signaling ELISA kit (Cell Signaling Path Scan phosphor pBAD ELISA)is utilized. 50 μL of the lysate is tested per the ELISA protocol andthe data analysis is performed by software on a SpectrMax5 plate reader(Molecular Devices, Sunnyvale, Calif.). IC₅₀ determination is performedby fitting the curve of percent inhibition versus the log of theinhibitor concentration using the GraphPad Prism 5.0 software.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

1-31. (canceled)
 32. A method of treating cancer comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: R¹ is selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ halaolkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a),C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a),NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a),C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a),NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a),S(O)NR^(a)R^(a), S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹ are eachoptionally substituted with 1, 2, 3, or 4 R^(b) substituents; each R^(b)substituent is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are eachoptionally substituted with 1-3 independently selected R^(d)substituents; or two adjacent R^(b) substituents on the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl or 4-10 memberedheterocycloalkyl ring of R¹, taken together with the atoms to which theyare attached, form a fused phenyl ring, a fused 5- or 6-memberedheterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring, or afused C₅₋₆ cycloalkyl ring, wherein the fused 5- or 6-memberedheterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring eachhave 1-4 heteroatoms as ring members selected from N, O and S andwherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkylring, fused 5- or 6-membered heteroaryl ring, and fused C₅₋₆ cycloalkylare each optionally substituted with 1 or 2 independently selected R^(r)substituents; each R^(a) is independently selected from H, CN, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents; each R^(d) is independentlyselected C₁₋₄ alkyl, C₁₋₄haloalkyl, halo, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, CN, NH₂, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl and 4-10membered heterocycloalkyl of R^(d) are each further optionallysubstituted with 1-3 independently selected R^(r) substituents; eachR^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl,4-10 membered heteroacycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heteroacycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄alkyl-, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents independently selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, R^(o), NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o),NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o),S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o),NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o); each R^(g) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋10 aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are each optionallysubstituted with 1-3 independently selected R^(p) substituents; or anytwo R^(a) substituents together with the nitrogen atom to which they areattached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 R^(h) substituentsindependently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ halaolkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i),C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i),NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i),NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i),S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i), NR^(i)S(O)₂R^(i),NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6membered heteroaryl of R^(h) are each further optionally substituted by1, 2, or 3 substituents independently selected from C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, C₁₋₄ alkenyl, C₂₋₄ alkynyl,halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k), SR^(k),C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k),NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k),NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k), NR^(k)C(═NR^(k))NR^(k)R^(k),S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k),NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k); or two R^(h) groupsattached to the same carbon atom of the 4- to 10-memberedheterocycloalkyl taken together with the carbon atom to which theyattach form a C₃₋₆ cycloalkyl or 4- to 6-membered heterocycloalkylhaving 1-2 heteroatoms as ring members selected from O, N or S or anytwo R^(c) substituents together with the nitrogen atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 independently selected R^(h)substituents; or any two R^(e) substituents together with the nitrogenatom to which they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(g) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with1, 2, or 3 independently selected R^(h) substituents; or any two R^(i)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; or any two R^(o) substituents together with thenitrogen atom to which they are attached form a 4-, 5-, 6-, or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; and each R^(e), R^(i), R^(k),R^(o)or R^(p) is independently selected from H, C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, C₁₋₄ haloalkyl,C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, C₁₋₄ alkenyl, and C₂₋₄ alkynylof R^(e), R^(i), R^(k), R^(o) or R^(p) are each optionally substitutedwith 1, 2 or 3 R^(r) substituents; each R^(r) is independently selectedfrom OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₃₋₆cycloalkyl, NHR⁹, NR⁹R⁹, and C₁₋₄ haloalkoxy, wherein the C₁₋₄ alkyl ofR^(r) is optionally substituted with OH, CN, NH₂, C₁₋₄ alkoxy, C₃₋₁₀cycloalkyl, and 4-10 membered heterocycloalkyl, wherein each R⁹ isindependently H or C₁₋₆ alkyl; R² is H, OH, OR^(a), NHR^(a) orNR^(a)R^(a); R³ is H, halo or CN; each R⁴ is independently selected fromH, halo, CN, OH, NH₂, NHCH₃, N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄alkoxy,C₁₋₂haloalkyl, C₁₋₂ halaolkoxy, ethenyl, C₂₋₄ alkynyl and cyclopropyl,wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionally substitutedwith CN or CH₃O—; each R⁵ is independently selected from H, halo, CN,OH, NH₂, NHCH₃, N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₂ haloalkoxy,ethenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, and 5- or 6-memberedheteroaryl, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionallysubstituted with CN or CH₃O—; each R⁶ is independently selected from H,halo, CN, OH, NH₂, NHCH₃, N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄alkoxy,C₁₋₂haloalkyl, C₁₋₂ haloalkoxy, ethenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, and 5- or 6-membered heteroaryl, wherein the C₁₋₄ alkyl,C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, and 5- or 6-memberedheteroaryl are each optionally substituted with OH, CN or CH₃O—; or anytwo R⁶ substituents attached to the same carbon atom, taken togetherwith the carbon atom to which they are attached, form C₃₋₁₀ cycloalkylor a 4-, 5-, or 6-membered heterocycloalkyl, wherein the C₃₋₁₀cycloalkyl and 4-, 5-, or 6-membered heterocycloalkyl are eachoptionally substituted with 1-3 independently selected R^(p)substituents; R⁸ is H, C₁₋₄ alkyl, C₃₋₆ cycloalkl, C₃₋₆ cycloalkl-C₁₋₄alkyl-, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl and C₃₋₆ cycloalkyl-C₁₋₄alkyl are each optionally substituted with OH, CN or CH₃O—; X is N orCR⁷, wherein R⁷ is H, halo, NH₂, C₁₋₄ alkoxy, C₁₋₄ alkyl-NH— or (C₁₋₄alkyl)₂N—; the subscript m is an integer of 1 or 2; the subscript n isan integer of 1, 2 or 3; and the subscript p is an integer of 1, 2 or 3.33. The method of claim 32 wherein the activity of at least one of Pim1,Pim2 and Pim3 is upregulated in the cancer.
 34. The method of claim 32wherein the cancer is prostate cancer, colon cancer, esophageal cancer,endometrial cancer, ovarian cancer, uterine cancer, renal cancer,hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lungcancer, cancer of the head or neck, thyroid cancer, glioblastoma,sarcoma, bladder cancer, lymphoma, leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia, chronic lymphocytic leukemia,chronic myelogenous leukemia, diffuse large-B cell lymphoma, mantle celllymphoma, non-Hodgkin lymphoma, Hodgkin lymphoma or multiple myeloma.35. A method of treating a myeloproliferative disorder, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: R¹ is selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ halaolkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a),C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a),NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a),C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a),NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a),S(O)NR^(a)R^(a), S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹ are eachoptionally substituted with 1, 2, 3, or 4 R^(b) substituents; each R^(b)substituent is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c)and S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are eachoptionally substituted with 1-3 independently selected R^(d)substituents; or two adjacent R^(b) substituents on the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl or 4-10 memberedheterocycloalkyl ring of R¹, taken together with the atoms to which theyare attached, form a fused phenyl ring, a fused 5- or 6-memberedheterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring, or afused C₅₋₆ cycloalkyl ring, wherein the fused 5- or 6-memberedheterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring eachhave 1-4 heteroatoms as ring members selected from N, O and S andwherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkylring, fused 5- or 6-membered heteroaryl ring, and fused C₅₋₆ cycloalkylare each optionally substituted with 1 or 2 independently selected R^(r)substituents; each R^(a) is independently selected from H, CN, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆-₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of IV are each optionally substituted with1, 2, 3, 4, or 5 R^(d) substituents; each R^(d) is independentlyselected C₁₋₄alkyl, C₁₋₄ haloalkyl, halo, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, CN, NH₂, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₄ alk_(y)l, C₃₋₁₀ cycloalkyl and4-10 membered heterocycloalkyl of R^(d) are each further optionallysubstituted with 1-3 independently selected R^(r) substituents; eachR^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heteroc cloalk C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl,4-10 membered heteroacycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents independently selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, R^(o), NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o),NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o),S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o),NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o); each R^(g) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl,4-10 membered heteroacycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are eachoptionally substituted with 1-3 independently selected R^(p)substituents; or any two IV substituents together with the nitrogen atomto which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆halaolkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i),NHOR^(i), C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i),OC(O)NR^(i)R^(i), NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i),NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i),NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i),NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), whereinthe C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-6 membered heteroaryl of R^(h) are each further optionallysubstituted by 1, 2, or 3 R^(j) substituents independently selected fromC₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k),SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k); or twoR^(h) groups attached to the same carbon atom of the 4- to 10-memberedheterocycloalkyl taken together with the carbon atom to which theyattach form a C₃₋₆ cycloalkyl or 4- to 6-membered heterocycloalkylhaving 1-2 heteroatoms as ring members selected from O, N or S; or anytwo R^(c) substituents together with the nitrogen atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 independently selected R^(h)substituents; or any two Re substituents together with the nitrogen atomto which they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(g) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with1, 2, or 3 independently selected R^(h) substituents; or any two R^(i)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; or any two R^(o) substituents together with thenitrogen atom to which they are attached form a 4-, 5-, 6-, or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; and each R^(e), R^(i), R^(k),R^(o) or R^(p) is independently selected from H, C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, C₁₋₄ haloalkyl,C₁₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, C₁₋₄ alkenyl, and C₂₋₄ alkynylof R^(e), R^(k), R^(o) or R^(p) are each optionally substituted with 1,2 or 3 R^(r) substituents; each R^(r) is independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₃₋₆cycloalkyl, NHR⁹, NR⁹R⁹, and C₁₋₄ haloalkoxy, wherein the C₁₋₄ alkyl ofR^(r) is optionally substituted with OH, CN, NH₂, C₁₋₄ alkoxy, C₃₋₁₀cycloalkyl, and 4-10 membered heterocycloalkyl, wherein each R⁹ isindependently H or C₁₋₆ alkyl; R² is H, OH, OR^(a), NHR^(a) orNR^(a)R^(a); R³ is H, halo or CN; each R⁴ is independently selected fromH, halo, CN, OH, NH₂, NHCH₃, N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄alkoxy,C₁₋₂haloalkyl, C₁₋₂ halaolkoxy, ethenyl, C₂₋₄ alkynyl and cyclopropyl,wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionally substitutedwith CN or CH₃O—; each R⁵ is independently selected from H, halo, CN,OH, NH₂, NHCH₃, N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₂ haloalkoxy,ethenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, and 5- or 6-memberedheteroaryl, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionallysubstituted with CN or CH₃O—; each R⁶ is independently selected from H,halo, CN, OH, Nth, NHCH₃, N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₂haloalkoxy, ethenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, and 5-or 6-membered heteroaryl, wherein the C₁₋₄ alkyl, C₁₋₄ alkoxy, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, and 5- or 6-membered heteroaryl are eachoptionally substituted with OH, CN or CH₃O—; or any two R⁶ substituentsattached to the same carbon atom, taken together with the carbon atom towhich they are attached, form C₃₋₁₀ cycloalkyl or a 4-, 5-, or6-membered heterocycloalkyl, wherein the C₃₋₁₀ cycloalkyl and 4-, 5-, or6-membered heterocycloalkyl are each optionally substituted with 1-3independently selected R^(p) substituents; R⁸ is H, C₁₋₄ alkyl, C₃₋₆ ccloalk 1 C₃₋₆ cycloalkyl-C₁₋₄ alkyl-, wherein the C₁₋₄ alkyl, C₃₋₆cycloalkyl and C₃₋₆ cycloalkyl-C₁₋₄ alkyl are each optionallysubstituted with OH, CN or CH₃O—; X is N or CR⁷, wherein R⁷ is H, halo,NH₂, C₁₋₄ alkoxy, C₁₋₄ alkyl-NH— or (C₁₋₄ alkyl)₂N—; the subscript m isan integer of 1 or 2; the subscript n is an integer of 1, 2 or 3; andthe subscript p is an integer of 1, 2 or
 3. 36. A method of treating animmune disorder comprising administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: R¹ is selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ halaolkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a),C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a),NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a),C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a),NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a),R^(a), S(O)R^(a),S(O)NR^(a)R^(a), S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹ are eachoptionally substituted with 1, 2, 3, or 4 R^(b) substituents, each R^(b)substituent is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, C₃₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)NR^(c)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are eachoptionally substituted with 1-3 independently selected R^(d)substituents; or two adjacent R^(b) substituents on the C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl or 4-10 memberedheterocycloalkyl ring of R¹, taken together with the atoms to which theyare attached, form a fused phenyl ring, a fused 5- or 6-memberedheterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring, or afused C₅₋₆ cycloalkyl ring, wherein the fused 5- or 6-memberedheterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring eachhave 1-4 heteroatoms as ring members selected from N, O and S andwherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkylring, fused 5- or 6-membered heteroaryl ring, and fused C₅₋₆ cycloalkylare each optionally substituted with 1 or 2 independently selected R^(r)substituents; each R^(a) is independently selected from H, CN, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents; each R^(d) is independentlyselected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, CN, NH₂, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), wherein the C₁₋₄ alk_(y)l, C₃₋₁₀ cycloalkyl and4-10 membered heterocycloalkyl of R^(d) are each further optionallysubstituted with 1-3 independently selected R^(r) substituents; eachR^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10membered heteroaryl,4-10 membered heteroacycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl,4-10 membered heteroacycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents independently selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, R^(o), NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o),NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o),S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o),NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o); each R^(g) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl,4-10 membered heteroacycloalkyl, C₆₋₁₀ aryl, C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of Rg are each optionallysubstituted with 1-3 independently selected R^(p) substituents; or anytwo R^(a) substituents together with the nitrogen atom to which they areattached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 R^(h) substituentsindependently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ halaolkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i),C(O)NR^(i)R^(i), C(O)NRilti, C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i),NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i),NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i),S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i), NR^(i)SO₂R^(i),NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-6membered heteroaryl of R^(h) are each further optionally substituted by1, 2, or 3 substituents independently selected from C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, C₁₋₄ alkenyl, C₂₋₄ alkynyl,halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k), OR^(k), SR^(k),C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k),NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k),NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k), NR^(k)C(═NR^(k))NR^(k)R^(k),S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k),NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k); or two R^(h) groupsattached to the same carbon atom of the 4- to 10-memberedheterocycloalkyl taken together with the carbon atom to which theyattach form a C₃₋₆ cycloalkyl or 4- to 6-membered heterocycloalkylhaving 1-2 heteroatoms as ring members selected from O, N or S; or anytwo R^(c) substituents together with the nitrogen atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 independently selected R^(h)substituents; or any two R^(e) substituents together with the nitrogenatom to which they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(g) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with1, 2, or 3 independently selected R^(h) substituents; or any two R^(i)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; or any two R^(o) substituents together with thenitrogen atom to which they are attached form a 4-, 5-, 6-, or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; and each R^(e), R^(i), R^(k),R^(o) or R^(p) is independently selected from H, C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, C₁₋₄ haloalkyl,C₁₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5- or 6-membered heteroaryl, C₁₋₄ alkenyl, and C₂₋₄ alkynylof R^(e), R^(i), R^(k), R^(o) or R^(p) are each optionally substitutedwith 1, 2 or 3 R^(r) substituents; each R^(r) is independently selectedfrom OH, CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₃₋₆cycloalkyl, NHR⁹, NR⁹R⁹, and C₁₋₄ haloalkoxy, wherein the C₁₋₄ alkyl ofR^(r) is optionally substituted with OH, CN, NH₂, C₁₋₄ alkoxy, C₃₋₁₀cycloalkyl, and 4-10 membered heterocycloalkyl, wherein each R⁹ isindependently H or C₁₋₆ alkyl; R² is H, OH, OR^(a), NHR^(a) orNR^(a)R^(a); R³ is H, halo or CN; each R⁴ is independently selected fromH, halo, CN, OH, NH₂, NHCH₃, N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄alkoxy,C₁₋₂haloalkyl, C₁₋₂ halaolkoxy, ethenyl, C₂₋₄ alkynyl and cyclopropyl,wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy are each optionally substitutedwith CN or CH₃O—; each R⁵ is independently selected from H, halo, CN,OH, NH₂, NHCH₃, N(CH₃)₂, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₂ haloalkyl, C₁₋₂haloalkoxy, ethenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, and 5-or 6-membered heteroaryl, wherein the C₁₋₄ alkyl and C₁₋₄ alkoxy areeach optionally substituted with CN or CH₃O—; each R⁶ is independentlyselected from H, halo, CN, OH, NH₂, NHCH₃, N(CH₃)₂, C₁₋₄ alkyl,C₁₋₄alkoxy, C₁₋₂ qhaloalkoxy, ethenyl, C₂₋₄ alkynyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, and 5- or 6-membered heteroaryl, wherein the C₁₋₄ alkyl,C₁₋₄ alkoxy, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, and 5- or 6-memberedheteroaryl are each optionally substituted with OH, CN or CH₃O—; or anytwo R⁶ substituents attached to the same carbon atom, taken togetherwith the carbon atom to which they are attached, form C₃₋₁₀ cycloalkylor a 4-, 5-, or 6-membered heterocycloalkyl, wherein the C₃₋₁₀cycloalkyl and 4-, 5-, or 6-membered heterocycloalkyl are eachoptionally substituted with 1-3 independently selected R^(p)substituents; R⁸ is H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄alkyl-, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl and C₃₋₆ cycloalkyl-Ch4alkyl are each optionally substituted with OH, CN or CH₃O—; X is N orCR⁷, wherein R⁷ is H, halo, NH₂, C₁₋₄ alkoxy, C₁₋₄ alkyl-NH— or (C₁₋₄alkyl)₂N—; the subscript m is an integer of 1 or 2; the subscript n isan integer of 1, 2 or 3; and the subscript p is an integer of 1, 2 or 3.37. The method of claim 36 wherein the immune disorder is an autoimmunedisease.
 38. A method of treating atherosclerosis comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of claim 32 or a pharmaceutically acceptable saltor a stereoisomer thereof.
 39. A method of reducing angiogenesis ortumor metastasis, comprising administering to a patient in need thereofa therapeutically effective amount of a compound of claim 32, or apharmaceutically acceptable salt or a stereoisomer thereof.
 40. Themethod of claim 32 wherein, the cancer is acute myelogenous leukemia.41. The method of claim 32, wherein the cancer is diffuse large-B celllymphoma.
 42. The method of claim 35, wherein the myeloproliferativedisorder is polycythemia vera, essential thrombocythemia, chronicmyelogenous leukemia, myelofibrosis, primary myelofibrosis,post-polycythemia vera/essential thrombocythemia myelofibrosis,post-essential thrombocythemia myelofibrosis or post-polycythemia veramyelofibrosis.
 43. The method of claim 32, the compound having formula(III):

or a pharmaceutically acceptable salt or a stereoisomer thereof.
 44. Themethod of claim 32, wherein the compound is selected from:N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-ethyl-5-fluoroquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(3R)-3-fluoropiperidin-1-yl]quinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-pyrrolidin-1-ylquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-azetidin-1-yl-5-fluoroquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(3S)-3-fluoropyrrolidin-1-yl]quinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(3R)-3-fluoropyrrolidin-1-yl]quinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-[(3S)-3-cyanopyrrolidin-1-yl]-5-fluoroquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-[(3R)-3-cyanopyrrolidin-1-yl]-5-fluoroquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-(3-fluoroazetidin-1-yl)quinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-morpholin-4-ylquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(3S)-3-methoxypiperidin-1-yl]quinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(3S)-3-methoxypiperidin-1-yl]quinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-cyclopropyl-5-fluoroquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(cyclopropylethynyl)-5-fluoroquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(2-cyano-6-fluorophenyl)-5-fluoroquinoline-8-carboxamide;tert-Butyl {(1S,3R,5S)-3-[3-({[3-(2,6-difluorophenyl)-5-fluoroquinolin-8-yl]carbonyl}amino)pyridin-4-yl]-5-methylcyclohexyl}carbamate;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(2-cyanophenyl)-5-fluoroquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(2,6-difluoro-4-hydroxyphenyl)-5-fluoroquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-[(cyclopropylmethyl)(methyl)amino]-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(ethyl(methyl)amino)-5-fluoroquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[methyl(2,2,2-trifluoroethyl)amino]quinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(2-fluoroethyl)(methyl)amino]quinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[methyl(tetrahydrofuran-3-yl)amino]quinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-[cyclobutyl(methyl)amino]-5-fluoroquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(dimethylamino)-5-fluoroquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(2-fluoroethyl)amino]quinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-[(2,2-difluoroethyl)amino]-5-fluoroquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-(3,3-difluoropiperidin-1-yl)-5-fluoroquinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(3S,4S)-3-fluoro-4-hydroxypiperidin-1-yl]quinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-(4-methylpiperazin-1-yl)quinoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-(tetrahydro-2H-pyran-4-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-3-methylmorpholino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-3-methylmorpholino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2,5-dimethylmorpholino)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2,5-dimethylpyrrolidin-1-yl)-5-fluoroquinoline-8-carboxami de;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2,6-dimethylmorpholino)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-2-methylmorpholino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(4,4-difluoropiperidin-1-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-hydroxy-4-methylpiperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((2,2-difluoroethyl)(methyl)amino)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(2-methylpiperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-hydroxypiperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(4-cyanopiperidin-1-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-methylpiperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-2-(methoxymethyl)pyrrolidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-2-(methoxymethyl)pyrrolidin-1-yl)quinoline-8-carboxamideN-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-3-methoxypyrrolidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-3-methoxypyrrolidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2-methoxyethyl)(methyl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((S)-1-cyclopropylethylamino)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-3-methylbutan-2-ylamino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-3-methylbutan-2-ylamino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl(propyl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(isopropyl(methyl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2-ethylpiperidin-1-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2-(difluoromethyl)piperidin-1-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5,6′-difluoro-3,8′-biquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5,5′-difluoro-3,8′-biquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(6-(trifluoromethyl)pyridin-3-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(1-ethyl-1H-pyrazol-4-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(1,3-dimethyl-1H-pyrazol-4-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(1-methyl-1H-pyrazol-4-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(3-methyl-1H-pyrazol-4-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(1H-pyrazol-4-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((R)-3-methylmorpholino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((R)-2-methylpyrrolidin-C₁₋₆-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((S)-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2-methylpiperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2-(difluoromethyl)piperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((2,2-difluoroethyl)(methyl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-thiomorpholinoquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(4-(N,N-dimethylsulfamoyl)piperazin-1-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-methyl-3-oxopiperazin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(azepan-1-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(2-oxopyrrolidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(indolin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(4-(dimethylcarbamoyl)piperazin-1-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl(phenyl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-2-methyl-4-(methylsulfonyl)piperazin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((1R,4R)-5-(methylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinoline-8-carboxamide;(9-Methyl4-(8-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-ylcarbamoyl)-5-fluoroquinolin-3-yl)-3-methylpiperazine-1-carboxylate;(R)-Methyl4-(8-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-ylcarbamoyl)-5-fluoroquinolin-3-yl)-3-methylpiperazine-1-carboxylate;(1R,4R)-Methyl5-(8-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-ylcarbamoyl)-5-fluoroquinolin-3-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;N-{4-[(1R,3S,5S)-3-amino-5-methylcyclohexyl]pyridin-3-yl}-3-(2,6-difluorophenyl)-5-fluorocinnoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-3-ethyl-5-fluorocinnoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-(2-methylpiperidin-1-yl)cinnoline-8-carboxamide;N-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(3R)-3-methylmorpholin-4-yl]cinnoline-8-carboxamide;andN-{4-[(1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(2R)-2-methylpyrrolidin-1-yl]cinnoline-8-carboxamide;or a pharmaceutically acceptable salt thereof.
 45. The method of claim32, wherein the compound is selected from:N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2-azabicyclo[2.2.1]heptan-2-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2-fluorophenyl)(methyl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((R)-2,4-dimethyl-5-oxopiperazin-1-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-4-oxodihydro-1H-pyrido[1,2-a]pyrazin-2(6H,7H,8H,9H,9aH)-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-methoxyazepan-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(1,4-oxazepan-4-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(6-hydroxy-2-azaspiro[3.3]heptan-2-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-hydroxyazepan-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-3-methylpiperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(2-azaspiro[3.3]heptan-2-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((3S,4S)-3-fluoro-4-hydroxypiperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(1,2-oxazinan-2-yl)quinoline-8-carboxamide;N-(4-((1R, 3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(dihydro-1H-furo[3,4-c]pyrrol-5(3H, 6H,6aH)-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(3-methylazetidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((S)-2,4-dimethyl-3-oxopiperazin-1-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-3-methylpiperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(4-cyclopropyl-3-oxopiperazin-1-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-isopropyl-3-oxopiperazin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(3,3-dimethylazetidin-1-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-isobutyl-3-oxopiperazin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(3-methoxy-3-methylazetidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(2-methyl-6,7-dihydro-2H-pyrazolo[4,3-c]pyridin-5(4H)-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(5-fluoro-2H-benzo[b][1,4]oxazin-4(3H)-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(3-ethoxyazetidin-1-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-2-(hydroxymethyl)azetidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-(methylsulfonyl)-1,4-diazepan-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(2-fluorophenylamino)quinoline-8-carboxamide;Methyl4-(8-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-ylcarbamoyl)-5-fluoroquinolin-3-yl)-1,4-diazepane-1-carboxylate;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(1-methyl-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(6-methyl-1,1-dioxido-1,2,6-thiadiazinan-2-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(2-cyanophenylamino)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5′-fluoro-3,4-dihydro-2H-1,3′-biquinoline-8′-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-methoxypiperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(2-(hydroxymethyl)morpholino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-(2-methoxyethyl)-3-oxopiperazin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(4-methyl-3-oxo-1,4-diazepan-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(7-azabicyclo[2.2.1]heptan-7-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5′,8-difluoro-3,4-dihydro-2H-1,3′-biquinoline-8′-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-(1,1-dioxidoisothiazolidin-2-yl)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((3-(difluoromethoxy)pyridin-2-yl)(methyl)amino)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((2-cyanocyclopentyl)(methyl)amino)-5-fluoroquinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-3-((2,6-dimethylpyridin-3-yl)(methyl)amino)-5-fluoroquinoline-8-carboxamide;-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((3-fluoropyridin-2-yl)(methyl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl(4-(trifluoromethyl)pyridin-3-yl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((6-methoxy-2-methylpyridin-3-yl)(methyl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((3-fluoropyridin-4-yl)(methyl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl(4-methylpyridin-3-yl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl(2-methylcyclobutyl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((4-methoxyphenyl)(methyl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl(3-methylpyrazin-2-yl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((4-methoxypyridin-3-yl)(methyl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl(tetrahydro-2H-pyran-3-yl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2-methoxyphenyl)(methyl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(imidazo[1,2-c]pyridin-6-yl(methyl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-(methyl((R)-tetrahydrofuran-3-yl)amino)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(2S,4R)-4-methoxy-2-methylpyrrolidin-1-yl]quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2R,4R)-4-methoxy-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2S,4S)-4-methoxy-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2R,4S)-4-methoxy-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2R,4S)-4-methoxy-2-methylpiperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2S,4R)-4-methoxy-2-methylpiperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2R,4R)-4-methoxy-2-methylpiperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((3R,4R)-3-fluoro-4-methoxypiperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((3S,4S)-3-fluoro-4-(2-methoxyethoxy)piperidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl]pyridin-3-yl}-5-fluoro-3-[(2R,4S)-4-hydroxy-2-methylpyrrolidin-1-yl]quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((2S,4S)-4-hydroxy-2-methylpyrrolidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-2-methylazetidin-1-yl)quinoline-8-carboxamide;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-2-methylazetidin-1-yl)quinoline-8-carboxamide;Ethyl4-(8-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-ylcarbamoyl)-5-fluoroquinolin-3-yl)piperazine-1-carboxylate;N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((R)-2-methylpiperidin-1-yl)quinoline-8-carboxamide;andN-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-5-fluoro-3-((S)-2-methylpiperidin-1-yl)quinoline-8-carboxamide;or a pharmaceutically acceptable salt thereof.